To see the other types of publications on this topic, follow the link: Axon development.
Dissertations / Theses on the topic 'Axon development'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 dissertations / theses for your research on the topic 'Axon development.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse dissertations / theses on a wide variety of disciplines and organise your bibliography correctly.
1
Wyatt, Cameron. "Optic axon guidance during development and regeneration in the zebrafish." Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/5947.
Full textAbstract:
Directed regeneration of axons in the CNS has potential for the treatment of CNS disorders and injuries. In contrast to mammals, following optic nerve lesion zebrafish regenerate axons that navigate to their correct targets and form new synapses leading to functional recovery. Correct pathfinding is thought to rely on a range of molecular cues in the CNS which the growing axon expresses receptors for. However, the specific guidance cues are not well elucidated. It is likely that a proportion of them will be the same as during development, while some may be specific to regeneration. Alternatively, axons may simply retrace former trajectories guided by the molecular environment or mechanical constraints of degenerating tracts, as demonstrated in the mammalian PNS. To elucidate this, we investigated regeneration in the astray/robo2 knockout mutant which exhibits misprojection of optic axons during development leading to the establishment of ectopic tracts. We show that degenerating tracts do not provide a strong guidance cue for regenerating axons in the CNS as ectopic tracts in the astray mutant are not repopulated following lesion despite presenting a similar environment to entopic degenerating tracts. We also find that as astray mutant (knockout) and robo2 morphant (transient knockdown) projection and termination errors persist in the adult, it is clear that there is not an efficient correction mechanism for large-scale pathfinding errors of optic axons during development. In addition, we find a reduced importance of the axon guidance receptor Robo2 and its repellent ligand Slit2 for pathfinding during regeneration as specific developmental pathfinding errors of optic axons in astray mutants are corrected during adult optic nerve regeneration and global overexpression of Slit2 elicits pathfinding defects during development but not regeneration. To address regeneration-associated gene regulation in axotomised retinal ganglion cells, we carried out a microarray analysis. We found that many genes detected as a gradient in the adult retina during regeneration are not differentially expressed in the embryonic eye, despite having distinct expression patterns in other embryonic tissues. Of the genes which exhibit strong differential expression in the retina of both regenerating adults and developing embryos, foxI1 is one of the most interesting candidates as other fox genes have been implicated in axon guidance and due to its highly restricted retinal expression pattern. Surprisingly, further investigation has revealed that foxI1 knockout mutant embryos have retinotectal projections which appear normal in terms of axon pathfinding and mapping. Another family of genes indicated by the array, which are cytosolic phosphoproteins known to be involved in the signal transduction cascade of multiple inhibitory guidance cues during axon growth, are the crmps. Knocking down crmp2 with morpholinos during development resulted in a sparser innervation of the tectum with individual axons which trend towards having less complex arbors with shorter branches and reduced overall axon length. As a whole this work adds to our current knowledge of optic axon guidance during development and regeneration and the relative importance and effect of selected potential guidance cues, which may help toward informing future mammalian CNS regeneration research.
2
Lickiss, Thomas. "Development of directed initial axon outgrowth in the cerebral neocortex." Thesis, University of Oxford, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.543013.
Full text
3
Yeomans, Heather Jane. "Investigations into the functions of immunoglobulin like cell adhesion molecules during vertebrate neural development." Thesis, University of Sheffield, 2001. http://etheses.whiterose.ac.uk/5986/.
Full textAbstract:
During neural development, each neuron sends an axon out from its cell body. Extending axons are guided by interactions between environmental factors and axonal receptors for these factors. It has been suggested that certain proteins of the immunoglobulin-like superfamily are among the molecules involved in axon guidance. In particular, TAG-1, Ll and NrCAM have previously been implicated in the guidance of dorsal spinal commissural axons at the ventral midline region known as the floor plate. To establish whether these molecules have such roles in mice, the dorsal spinal axons of TAG-1, L1 or NrCAM mutant mouse embryos were traced. There were no significant differences between the results from mutant embryos and their wild type counterparts. This indicated that these three proteins are individually not essential for the normal development of mouse dorsal spinal projections. However, results from TAG-MLI double mutant embryos suggested that TAG- I and LI might affect the ability of commissural axons to extend out of the floor plate. Analysis of ephrin B3 mutant embryos indicated that ephrin B3 might also be important for floor plate exit. As the TAG-1 null mutation includes a lacZ construct, this reporter gene was used to further investigate the roles of TAG-1. Its expression was used to determine distribution of TAG-1 gene activity in the developing mouse nervous system. As the pattern of reporter expression was found to be comparable with that of TAG-1 protein, the TAG-1 null allele was used as a marker for TAG-1-expressing cells in mutant embryos. Most of the structures that normally express TAG-1 seemed to be unaffected by an absence of the protein. However, the hypoglossal nerve was significantly less likely to extend towards the tongue in TAG-1 null homozygous embryos than in heterozygotes. This suggested that TAG-1 might be important for the guidance of hypoglossal axons.
4
Ibrahim, Merdol. "Axon-oligodendrocyte relations in the anterior medullary velum of the rat brain." Thesis, King's College London (University of London), 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.263729.
Full text
5
Kamkar, Fatemeh. "Pftaire1 (Cyclin Dependent Kinase14): Role and Function in Axonal Outgrowth During the development of the CNS." Thesis, Université d'Ottawa / University of Ottawa, 2015. http://hdl.handle.net/10393/32860.
Full textAbstract:
Cyclin Dependent Kinase (Cdk) family members play a role in CNS development. Cyclin Dependent Kinase 5 (Cdk5) is well known for its fundamental role in neuronal development and axogenesis, as well as, cell death. Other Cdks include Pctaire and Pftaire. Inhibition of Pctaire results in increased axon outgrowth, however, the role and function of Pftaire is unknown. Pftaire1 is a novel member of the Cdk family that was initially detected in a screen for cdc2-like kinases. Unpublished data from our lab reveals that Pftaire1 (Eip63E) deficiency in Drosophila melanogaster results in defects in the axon and neuronal structure of the ventral nerve cord (VNC). In mammals, Pftaire1 is highly, expressed in the CNS. Here, we proposed that Pftaire1 might have a role in axon outgrowth. To investigate the role of Pftaire1 in mammals, the first germline Pftaire1 knockout mice were generated. Considering the severe effects of Eip63E deficiency in Drosophila and the homology between mammalian and fly Pftaire1, CNS defects in the mouse were anticipated. However, to date, no gross abnormalities have been detected in the overall morphology, fertility, life span, or anatomical brain structures of the Pftaire1 deficient mice. This may be due to the presence of other post-mitotic Cdk proteins that are highly similar to Pftaire1. For instance, mammals possess Pftaire (1, and 2), as well as, Pctaire (1, 2, and 3), while Drosophila only possess the Pftaire1 orthologue where the Pftaire2 and Pctaire (1, 2, and 3) are absent. Furthermore, the mice were of mixed background. In spite of this, we demonstrated that Pftaire1 deficient neurons showed increased axon length, in the initial phases of culture. This was confirmed by expression of dominant negative (DN) D228N-Pftaire1 in wild type neurons. Also classification of axons into different ranges, reveals a higher percentage of hyperextended neurites in D228N and Pftaire1 knockout mice. The mechanism by which Pftaire1 controls axon outgrowth is unknown. In this study we show that, Pftaire1 interacts physically with the small GTPase proteins Rac1, Cdc42, and RhoA. Importantly, we showed that Pftaire1 phosphorylates GDP-RhoA on a serine residue. We propose that this regulates RhoA activity, which in turn controls axon outgrowth.
6
Zhang, Ye. "The role of the secretory pathway in dendrite and axon development." Diss., Search in ProQuest Dissertations & Theses. UC Only, 2009. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3390087.
Full text
7
Wang, Xinshuo Snider William D. "Glycogen synthase kinase-3 is required for axon growth and development." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2009. http://dc.lib.unc.edu/u?/etd,2435.
Full textAbstract:
Thesis (M.S.)--University of North Carolina at Chapel Hill, 2009.Title from electronic title page (viewed Sep. 3, 2009). "... in partial fulfillment of the requirements for the degree of Master of Science in the Department of Cell and Molecular Physiology in School of Medicine." Discipline: Cell and Molecular Physiology; Department/School: Medicine.
8
Steinel, Martin C. "Flamingo/Starry night in embryonic abdominal sensory axon development of Drosophila /." Connect to thesis, 2008. http://repository.unimelb.edu.au/10187/3144.
Full text
9
Huberman, Andrew David. "Neural activity and axon guidance cue regulation of eye-specific retinogeniculate development /." For electronic version search Digital dissertations database. Restricted to UC campuses. Access is free to UC campus dissertations, 2004. http://uclibs.org/PID/11984.
Full text
10
Clegg, James Matthew. "Role of transcription factor Pax6 in the development of the thalamocortical tract." Thesis, University of Edinburgh, 2013. http://hdl.handle.net/1842/8099.
Full textAbstract:
During development the nuclei of the thalamus form reciprocal connections with specific regions within the cortex. These connections give rise to the thalamocortical tract. The processes by which axons of the thalamocortical tract are guided to their target regions are poorly understood. It has been shown that diffusible or membrane bound factors can have a chemoattractive or chemorepulsive effect on the tip or growth cone of the axon. Thalamocortical axons may also be guided along ‘pioneer’ axon populations that form a scaffold along which axons may grow. The transcription factor Pax6 has been shown to have a role in a variety of developmental processes such as neuronal patterning, proliferation, migration and axon guidance. It is known that Pax6 is involved in the development of the thalamocortical tract but its exact role is unknown. To explore the role that Pax6 plays in the development of the thalamocortical tract I have used two different mouse models, the small eye (Pax6Sey/Sey) mouse which lacks functional Pax6, and a conditional Pax6 knock-out (Pax6cKO) mouse made using a Gsh2 Cre line that specifically reduces Pax6 expression in the ventral telencephalon and prethalamus. Using the Pax6Sey/Sey mouse I show that thalamocortical axons do not enter the ventral telencephalon in the absence of Pax6 and that a small number of axons incorrectly enter the hypothalamus. In addition axons found within the ventral telencephalon of the mutant do not originate from the thalamus but instead originate from cells within the ventral telencephalon itself. I have found that the expression of guidance molecule Robo2 is reduced in the Pax6Sey/Sey mouse, which may explain why thalamocortical axons enter the hypothalamus. When Pax6 expression is reduced at the prethalamus and ventral telencephalon using the Pax6cKO mouse I show that the majority of thalamocortical axons reach the cortex normally but some axons become disorganized within the thalamus. Pioneer axons which emanate from the prethalamus normally guide thalamocortical axons through the diencephalon but in the Pax6cKO I report that these axons are reduced which may explain the disorganization of thalamocortical axons within the thalamus. Taken together the data from these two models demonstrate that for the thalamocortical tract to form normally Pax6 expression is required in both the cells of the thalamus and in cells that lie along the route of the tract. In addition I provide evidence that Pax6 may influence axon guidance by controlling the expression of guidance molecules and the development of pioneer axon tracts.
11
Donovan, Lauren Janine. "CONTINUOUSLY ACTIVE TRANSCRIPTIONAL PROGRAMS ARE REQUIREDTO BUILD EXPANSIVE SEROTONERGIC AXON ARCHITECTURES." Case Western Reserve University School of Graduate Studies / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=case1567703887338716.
Full text
12
Hale, Laura Ann 1978. "Molecular mechanisms of zebrafish motoneuron development." Thesis, University of Oregon, 2009. http://hdl.handle.net/1794/10547.
Full textAbstract:
xv, 83 p. : ill. (some col.) A print copy of this thesis is available through the UO Libraries. Search the library catalog for the location and call number.This dissertation describes research to identify genes involved in specification, patterning and development of zebrafish primary motoneurons. We first examined the spatiotemporal expression patterns of retinoic acid and retinoid X receptor mRNAs to determine whether particular ones might be involved in motoneuron specification or patterning. Retinoic acid and retinoid X receptor mRNAs are expressed at the right time to pattern motoneurons, but the expression patterns did not suggest roles for particular receptors. In contrast, netrin mRNAs are expressed in specific motoneuron intermediate targets and knockdown experiments revealed an important role in development of VaP motoneurons. Two identified motoneurons, CaP and VaP, initially form an equivalence pair. CaPs extend long axons that innervate ventral muscle. VaPs extend short axons that stop at muscle fibers called muscle pioneers; VaPs later typically die. Previous work showed that during extension, CaP axons pause at several intermediate targets, including muscle pioneers, and that both CaP and muscle pioneers are required for VaP formation. We found that mRNAs for different Netrins are expressed in intermediate targets before CaP axon contact: netrin 1a in muscle pioneers, netrin 1b in hypochord, and netrin 2 in ventral somite. We show that Netrins are unnecessary to guide CaP axons but are necessary to prevent VaP axons from extending into ventral muscle. Netrin 1a is necessary to stop VaP axons at muscle pioneers, Netrin 1a and Netrin 2 together are necessary to stop VaP axons near the hypochord, and Netrin 1b appears dispensable for CaP and VaP development. We also identify Deleted in colorectal carcinoma as a Netrin receptor that mediates the ability of Netrin 1a to cause VaP axons to stop at muscle pioneers. Our results suggest Netrins refine axon morphology to ensure final cell-appropriate axon arborization. To learn whether Netrin proteins diffuse away from their sources of synthesis to function at a distance, we are developing Netrin antibodies. If successful, the antibodies will provide the research community at large with a new tool for understanding in vivo Netrin function. This dissertation includes both my previously published and unpublished coauthored material.
Committee in charge: Monte Westerfield, Chairperson, Biology Judith Eisen, Advisor, Biology; Victoria Herman, Member, Biology; John Postlethwait, Member, Biology; Clifford Kentros, Outside Member, Psychology
13
Zhong, Zhen. "Co-factors of LIM-HD transcription factors in neural development and axon pathfinding in zebrafish." Thesis, University of Edinburgh, 2012. http://hdl.handle.net/1842/8215.
Full textAbstract:
The zebrafish neuromuscular system is an elegant model to study neural development. To reveal a specific programme for zebrafish motor axon pathfinding I established a method to selectively block motor axon pathfinding by interfering with LIM domain transcription factor signaling. LIM homeodomain proteins (LIM-HDs) are an important class of transcriptional regulators and involved in neural development as well as neuron fate decision in vertebrates. DD domain dimerization of CLIM (cofactor of LIM-HDs) can activate LIM-HDs and downstream gene transcription while over-expression of dominant-negative CLIM (DN-CLIM), which lacks the DD domain, blocks LIM-HD activity. Motor neurons fluoresce in HB9:GFP transgenic zebrafish as the promoter of the motor neuron specific gene Hb9 drives expression of GFP. Motor axons in DN-CLIM injected HB9:GFP zebrafish are unable to exit the spinal cord, instead they grow inside the spinal cord. Thus axon pathfinding, but not general growth appears to be impaired in these neurons. This provides an excellent research model to find genes involved in motor axon pathfinding downstream of LIM-HDs. Gene array expression profiling was carried out on GFP+ motor neurons by fluorescence-activated flow sorting (FACS) with and without prior injection of DN-CLIM mRNA to elucidate the potential genes relevant to motor axon pathfinding. Genes that were most strongly down-regulated in DN-CLIM injected embryos were considered to belong to a motor axon specific guidance programme. Calca, tac-1 and chodl genes, retrieved from the gene array data, showed specific expression pattern in motor neuron and obvious down-regulation after DN-CLIM injection by in situ hybridization. This validated the array results. Chodl contains a C-type lectin domain representing a potential cell surface receptor for guidance factors. Gene knock-down experiments with two independent morpholinos led to stalling of CaP motor axons at the horizontal myoseptum, a pivotal choice point for axon pathfinding. This suggests that this novel gene specifically affects motor axon pathfinding in zebrafish. Single stranded DNA binding protein 1 (SSDP1) functions as an activator of SSDP1/CLIM/LIM-HD complex which involved in the transcriptional control of embryonic development. To verify how SSDP1 function in neural development in zebrafish, I have cloned Zebrafish SSDP1a and SSDP1b, which are most closely related to mouse and human SSDP1. SSDP1a is widely expressed during zebrafish development while SSDP1b is specifically expressed in sensory trigeminal and Rohon-Beard neurons. Over-expression of the N-terminal portion of SSDP1 (N-SSDP1) increases endogenous CLIM protein levels in vivo and impairs the formation of eyes and midbrain-hindbrain boundary. In addition, SSDP1b knock down impairs trigeminal and Rohon-Beard sensory axon growth. N-SSDP1 can partially rescue the inhibition of axon growth induced by DN-CLIM. These results reveal specific functions of SSDP1 in neural patterning and sensory axon growth which are in part due to the stabilization of LIM-HD/CLIM complexes. In summary, co-factors of LIM-HDs play important roles in neural development, cell fate specification as well as axon pathfinding.
14
Wissner-Gross, Zachary Daniel. "Symmetry Breaking in Neuronal Development." Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10639.
Full textAbstract:
Many physical systems break symmetry in their evolution. Biophysical systems, such as cells, developing organisms, and even entire populations, are no exception. Developing neurons represent a striking example of a biophysical system that breaks symmetry: neurons cultured in vitro begin as cell bodies with several tendrils (“neurites”) growing outward. A few days later, these same neurons invariably have the same new morphology: exactly one of the neurites (the “axon”) has grown hundreds of microns in length, while the others (the “dendrites”) are much shorter and are more branched. Previous work has shown that any of the neurites can become the axon, and so neurons must break symmetry during their development. The mechanisms underlying neuronal symmetry breaking and axon specification have recently attracted attention, with multiple groups proposing biophysical models to explain the phenomena. In this thesis, we perform the first analytical comparisons of these models by conducting multiple phenotypic and morphological studies of neurite growth in developing neurons. Studying neurite dynamics is technically challenging because neurites have unpredictable morphologies. In Chapter 4, we study neurite competition and neuronal symmetry breaking in hundreds of neurons by optically patterning micron-wide stripes to which the neurons adhere, and on which they grow exactly two neurites. We then use our measurements to test the accuracy of the models in the simple case when a neuron has exactly two neurites. In Chapter 5, we no longer constrain neuronal morphology. One characteristic of symmetry breaking systems is how the system’s complexity affects the symmetry breaking. We find that a majority of the models predict that neurons with more neurites break symmetry much slower than neurons with fewer neurites. Experimentally, we find that neurons with different neurite counts break symmetry at the same rate, consistent with previous observations. We then determine why the models disagree in their predictions, and rectify the models using our own experimental data. In particular, we find that neurons with higher neurite counts have higher concentrations of key proteins involved in symmetry breaking, so that neurons, regardless of neurite count, can break symmetry at the same rate.Physics
15
Liu, Rachel Qian. "Semaphorin 5B functions as a diffusible guidance cue to regulate sensory axon pathfinding during development." Thesis, University of British Columbia, 2012. http://hdl.handle.net/2429/42851.
Full textAbstract:
The centrally projecting sensory axons of the dorsal root ganglia follow a well established pattern that is conserved across many species and offers a robust model for the study of axonal guidance. When primary sensory axons leave the sensory ganglia and project to the embryonic spinal cord, they do not immediately extend into the spinal cord dorsal horn, but bifurcate and travel long the rostrocaudal axis of the animal to form the dorsal funiculus and Lissaur’s tract. At a later stage they extend collateral fibres that enter the dorsal horn and target to specific laminae according to their sensory modality. The factors that prevent immediate entry into the dorsal horn or regulate the timing of sensory collateral formation and specificity of lamina innervation have not been clearly identified. Our lab previously showed that Semaphorin5B (Sema5B), a member of the semaphorin family of guidance molecules, is dynamically expressed in the embryonic spinal cord and correlates with these sensory axon targeting events. Using in vitro assays, I show systematically that Sema5B inhibits growth of both nerve growth factor-responsive and neurotrophin-3-responsive dorsal root ganglion neurites and that this inhibitory effect on the former is mediated in part through the cell adhesion molecule TAG-1. Using the technique of RNA interference, I show in vivo that a reduction-of-function of Sema5B in the spinal cord leads to cutaneous axons not only projecting prematurely into, but to erroneous targets within the dorsal horn of the spinal cord, while proprioceptive axons continued to pathfind correctly. Together, these results suggest that Sema5B acts as a repulsive barrier for centrally projecting primary sensory axons that first reach the spinal cord, and once collaterals form, Sema5B exerts a differential function on different types of sensory fibres to regulate their pathfinding. This is the first study to identify the specific cue that regulates sensory neuron entry and guidance into the spinal cord dorsal horn grey matter.
16
Hammond, Rachel Alison. "The role of slits in the axon guidance of cranial motor neurons during hindbrain development." Thesis, King's College London (University of London), 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.408220.
Full text
17
Nugent, Alicia Anne. "Hyperactive alpha2-chimaerin reveals the complexity of axon guidance signaling pathways in motor neuron development." Thesis, Harvard University, 2016. http://nrs.harvard.edu/urn-3:HUL.InstRepos:33493414.
Full textAbstract:
α2-chimaerin has striking importance for proper neural circuit formation. Individuals with gain-of-function mutations in α2-chimaerin have Duane retraction syndrome, a common neurogenic eye movement disorder, and α2-chimaerin knockout mice have a rabbit-like hopping gait, resulting from aberrant motor neuron wiring. While molecular mechanisms underlying altered gait circuitry in the loss-of-function mouse have been characterized, mechanisms underlying the etiology of DRS caused by mutant CHN1 remain unclear.
Here, we report the first Chn1 gain-of-function DRS mouse model (Chn1-KI), which harbors a knock-in point mutation identified in human patients. Chn1-WT/KI and Chn1-KI/KI embryonic mice exhibit abducens nerve stalling, aberrant trochlear nerve branching, and first cervical spinal segment (C1) misrouting, which result from axon guidance defects. The Chn1-KI mouse recapitulates the human DRS phenotype, thus providing a novel mouse model of DRS. Chn1-KO/KO embryos display abducens nerve wandering and defasciculation, establishing that human DRS-causing mutations are indeed gain-of-function.
We combine detailed 3D whole embryo imaging with novel in vitro approaches to demonstrate that hyperactivated α2-chimaerin acts downstream of ephrin forward and reverse signaling selectively in abducens neurons to modulate nerve development, as C1 neurons use only ephrin forward signaling, and trochlear neurons do not significantly use ephrin signaling during nerve guidance. In vivo, we find that selectively removing ephrin forward or reverse signaling via EphA4 dramatically impacts the development of the abducens nerve, distinct from bidirectionally removing EphA4 signaling.
Further experimentation reveals that alpha2-chimaerin and EphA4 can signal through other pathways. We find that hyperactivated alpha2-chimaerin modulates BDNF, GDNF, NGF, and HGF signaling in vitro, thus suggesting its role as a broad regulator of axon guidance pathways. Our studies lend insight into the complexity of axon guidance during development and highlight mechanisms that cause the abducens nerve to be selectively vulnerable to alpha2-chimaerin misregulation in DRS.Medical Sciences
18
Chen, Lei. "The role of Cdc42 and Rac1 GTPases in mammalian forebrain development." Cincinnati, Ohio : University of Cincinnati, 2006. http://rave.ohiolink.edu/etdc/view.cgi?acc_num=ucin1163039225.
Full textAbstract:
Thesis (Ph. D.)--University of Cincinnati, 2006.Advisor: Yi Zheng. Title from electronic thesis title page (viewed Apr. 22, 2009). Keywords: Rho GTPase; forebrain; development; neuritogenesis; axon guidance; migration; polarity; patterning; holoprosencephaly. Includes abstract. Includes bibliographical references.
19
Magar, Manisha. "Opioid Addiction Treatments During Pregnancy and Their Effects on Axonal Growth and Myelination in the Developing Central Nervous System." VCU Scholars Compass, 2011. http://scholarscompass.vcu.edu/etd/244.
Full textAbstract:
Treatment with buprenorphine represents a promising alternative for pregnant opioid addicts but there is a need to understand potential effects on nervous system development. We previously showed effects of perinatal exposure to buprenorphine on axonal caliber and myelination in 26-day-old rat corpus callosum. These changes, detected at the end of rapid brain myelination and accompanied by earlier oligodendrocyte maturation, suggested interference with mechanisms coordinating axonal growth and myelination. To better understand buprenorphine actions and to establish whether these effects extend to the spinal cord, we analyzed the corpus callosum and corticospinal tract at 16 days of age, just before the peak of myelination. Our results point to an important role of the opioid system in regulating early axo-glial interactions coordinating axonal growth and myelination. Moreover, in addition to reinforcing previous findings in the brain, we showed for the first time that these effects are also exerted in the spinal cord.
20
Ensslen, Sonya Emily Lesya. "The role of signaling via the receptor tyrosine phosphatase PTPmu in retinal development and axon guidance." Connect to online version, 2004. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=case1080835127.
Full text
21
Roche, Sarah Louise. "Importance of axon-glial interactions for the normal postnatal development of the mouse peripheral nervous system." Thesis, University of Edinburgh, 2015. http://hdl.handle.net/1842/15888.
Full textAbstract:
The mouse nervous system undergoes a vast remodelling of synaptic connections postnatally, resulting in a reduced number of innervating axons to target cells within the first few weeks of life. This extensive loss of connections is known as synapse elimination and it plays a critical role in sculpting and refining neural connectivity throughout the nervous system, resulting in a finely tuned and well-synchronised network of innervation. This process has been well characterised at the mouse neuromuscular junction (NMJ), where synapse elimination takes place postnatally in all skeletal muscles. It has been well studied for the reasons that it is easily accessible for live imaging and post-mortem experimental analysis. Studies utilising this synapse to uncover regulators of synapse elimination have mainly focused on the importance of glial cell lysosomal activity, nerve conduction and target-derived growth factor supply. It is clear that non-axonal cell types play key roles in the success of developmental axon retraction at the NMJ, however the role of glial cells in the regulation of this process has not been fully explored, as lysosomal activity is thought of as a consequence of axon pruning rather than a molecular driver. Previous studies have shown that signals emanating from myelinating glial cells can modulate neurofilament composition and transport within the underlying axons. We know that these changes in neurofilament composition and transport are underway during developmental synapse elimination at the NMJ, so it seems logical to predict that myelinating glial cells may play a role in the regulation of axonal pruning. Myelinating glial cells are found along the entire length of lower motor neurons and form physical interactions with the underlying axons at regions known as paranodes. At the paranode, Neurofascin155 (Nfasc155: expressed by the myelinating glial cell) interacts with a Caspr/contactin complex (expressed by the axon). This site has been proposed as a likely site for axon-glial signalling due to the close apposition of the cell membranes. The main focus of this PhD project was to study the potential role of myelinating glial cells in the success of synapse elimination at the NMJ, using a mouse model of paranodal disruption (Nfasc155-/-). Chapters 3 and 4 show the results of this work. This work has revealed a novel role for glia in the modulation of synapse elimination at the mouse neuromuscular junction, mediated by Nfasc155 in the myelinating Schwann cell. Synapse elimination was profoundly delayed in Nfasc155-/- mice and was found to be associated with a non-canonical role for Nfasc155, as synapse elimination occurred normally in mice lacking the axonal paranodal protein Caspr. Loss of Nfasc155 was sufficient to disrupt axonal proteins contributing to cytoskeletal organisation and trafficking pathways in peripheral nerve of Nfasc155-/- mice and lower levels of neurofilament light (NF-L) protein in maturing motor axon terminals. Synapse elimination was delayed in mice lacking NF-L, suggesting that Nfasc155 influences neuronal remodelling, at least in part, by modifying cytoskeletal dynamics in motor neurons. This work provides the first clear evidence for myelinating Schwann cells acting as drivers of synapse elimination, with Nfasc155 playing a critical role in glial cell-mediated postnatal sculpting of neuronal connectivity in the peripheral nervous system. A small section of the results within this thesis are devoted to the study of axon-glial interactions in a mouse model of childhood motor neuron disease, otherwise known as spinal muscular atrophy (SMA). In SMA, there are reduced levels of the ubiquitously expressed survival motor neuron (SMN) protein. The NMJ is a particularly vulnerable target in SMA, manifesting as a breakdown of neuromuscular connectivity and progressive motor impairment. Recent studies have begun to shed light on the role of non-neuronal cell types in the onset and progression of the disease, presenting SMA as a multi-system disease rather than a purely neuronal disorder. Recent evidence has highlighted that myelinating glial cells are significantly affected in a mouse model of SMA, manifesting as an impaired ability to produce key myelin proteins, resulting in deficient myelination. The final results chapter of this thesis (Chapter 5) is focussed on further exploring the effects that loss of SMN has in Schwann cells including their interactions with underlying axons. This work reveals a disruption to axon-glial interaction, shown by a delay in the development of paranodes, supporting the idea that non-neuronal cell types are also affected in SMA. The results within this thesis reveal a novel role for a glial cell protein, Nfasc155, in the modulation of synapse elimination at the NMJ. Mechanistic insight in to Nfasc155’s role in this process is also uncovered and likely involves axonal cytoskeletal transport systems and the filamentous protein NF-L, which have not previously been implicated in the process of synapse elimination. This work highlights an important role for axon-glial interactions during normal postnatal development of the mouse NMJ. This work also highlights a role for axon-glial interactions in disease states of the NMJ. Using a mouse model of SMA, axon-glial interaction was assessed with the finding of a delay in paranodal maturation due to loss of SMN.
22
Mendes, Shannon. "Multiple B-Class Ephrins and EPH Receptors Regulate Midline Axon Guidance in the Developing Mouse Forebrain." Scholarly Repository, 2006. http://scholarlyrepository.miami.edu/oa_dissertations/49.
Full textAbstract:
Ephrins and Eph receptors have been implicated in a number of developmental processes including axon growth and guidance. One important guidepost is the central nervous system midline, where ephrins and Eph receptors have been implicated. At the embryonic midline, axons either cross into the contralateral central nervous system (CNS) targeting appropriate partners on the opposite side or remain ipsilateral extending either rostrally or caudally. In these studies, we examine a major forebrain commissure called the corpus callosum (CC). Agenesis of the CC is a rare birth defect that occurs in isolated conditions and in combination with other developmental cerebral abnormalities. Recent identification of families of growth and guidance molecules has generated interest in the mechanisms that regulate callosal growth. One family, ephrins and Eph receptors, has been implicated in mediating midline pathfinding decisions; however, the complexity of these interactions has yet to be unraveled. This dissertation sheds light on which B-class ephrins and Eph receptors function to regulate CC midline growth, and how these molecules interact with important guideposts during development. We also show that multiple Eph receptors (B1, B2, B3, and A4) and B-class ephrins (B1, B2, and B3) are present and function in developing forebrain callosal fibers based on both spatial and temporal expression patterns and analysis of gene-targeted knockout mice. Defects are most pronounced in the combination double knockout mice, suggesting that compensatory mechanisms exist for several of these family members. Furthermore, these CC defects range from mild hypoplasia to complete agenesis and Probst's bundle formation. Further analysis of the ephrinB3 gene revealed that Probst's bundle formation may reflect aberrant glial formations which alter the normal architecture of midline glia resulting in one potential mechanism of this abnormal phenotype. Another potential mechanism we discovered is a role for EphB1 receptor in the altered sensitivity of CC axons to midline guidance cues. Removal of this receptor resulted in cortical axons responding to GW guidepost cells with increased sensitivity. Our results support a significant role for ephrins and Eph receptors in CC development and may provide insight to possible mechanisms involved in axon midline crossing as well how failed molecular and genetic mechanisms may contribute to human CC disorders. Lastly, we show that one fiber tract that remains ipsilateral in the forebrain may use distinct midline guideposts to regulate proper growth and guidance. These findings implicate additional ephrins and Eph receptors in CC midline guidance than previously known and reveal novel mechanisms in mice, which may be pertinent to human disease states that result in agenesis of the CC.
23
Stovall, Elizabeth L. "Analysis of mig-10, a gene involved in nervous system development in caenorhabditis elegans." Link to electronic thesis, 2004. http://www.wpi.edu/Pubs/ETD/Available/etd-0430104-142249/.
Full text
24
Choi, Yong-Jin. "Function of commissureless and related genes in drosophila neural development." The Ohio State University, 2003. http://rave.ohiolink.edu/etdc/view?acc_num=osu1054558823.
Full text
25
Thompson, Amelia Joy. "In vivo and in vitro guidance of developing neurons by mechanical cues." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/279085.
Full textAbstract:
During nervous system development, growing axons navigate towards their targets using signals from their environment. These signals may be biochemical or mechanical in nature; however, the role of mechanical cues in axon pathfinding in vivo, and the spatiotemporal dynamics of embryonic brain mechanics, are still largely uncharacterised. Here, I have identified a role for tissue mechanics in embryonic axon guidance in vivo, using retinal ganglion cell (RGC) axon outgrowth in the developing Xenopus laevis optic tract (OT) as a model system. Using atomic force microscopy (AFM) to map brain stiffness in vivo, I found that embryonic Xenopus brain tissue was mechanically heterogeneous at both early and later stages of OT outgrowth, i.e. just before RGC axons make a stereotypical turn in the mid-diencephalon, and when they reach their target, respectively. The final path of RGC axon turning followed a clear mechanical gradient: by the later stage, tissue rostral to the OT had become stiffer than tissue caudal to it. This mid-diencephalic stiffness gradient was an intrinsic property of the underlying brain tissue, and correlated with local cell body densities (with higher density rostral to the OT and lower density caudal to it). Crucially, inhibiting cell proliferation in vivo during OT outgrowth abolished the stiffness gradient and reduced OT turning at the later stage. Next, I developed a time-lapse AFM technique to track tissue stiffness and RGC axon behaviour simultaneously in vivo. Using this approach, I followed the evolution of the mid-diencephalic stiffness gradient during intermediate developmental stages, around the time when the OT’s caudal turn is initiated. The stiffness gradient was shallow pre-turn, but increased in magnitude during axon turning (mostly due to an increase in tissue stiffness rostral to the OT). This increase in stiffness gradient preceded the rise in OT turning angle, suggesting that the stiffness gradient is not caused by the invading axons. The observed rise in stiffness gradient correlated with stage-specific increases in local cell density, and was attenuated by blocking mitosis in vivo during time-lapse AFM measurements (which also reduced OT turning). As final confirmation that brain stiffness contributes to RGC axon pathfinding, I disrupted mechanical gradients by artificially stiffening brain tissue in vivo. Importantly, global stiffening via application of transglutaminase eliminated the mid-diencephalic stiffness gradient by increasing tissue stiffness caudal of the OT, and reduced the OT turning angle. Sustained mechanical compression of small areas using an AFM probe stiffened brain locally and repelled RGC axons, consistent with the way they turned away from rapidly stiffening tissue regions during time-lapse AFM experiments. Taken together, these results are consistent with a function for tissue mechanics in axon pathfinding in vivo.
26
Teng, Teng. "Molecular guidance of serotonin raphe neurons during development." Thesis, Paris 6, 2016. http://www.theses.fr/2016PA066584/document.
Full textAbstract:
Sérotonine (5-HT) neurones du mésencéphale sont nés de jour embryonnaire 10 à 12, et commencent à étendre axones, peu après la neurogenèse, tant rostrale du télencéphale et caudale du tronc cérébral. Ces projections sont très garantis, mais avec un certain degré d'organisation topographique. Dans le télencéphale, le schéma de la 5-HT innervation provenant de la dorsale (B7, B6) ou de la médiane (B5-B8) se distingue des noyaux. Cependant, il n'y a pas d'études de développement détaillées systématiques chez la souris, qui sont le modèle le plus largement utilisé, en particulier pour les études génétiques. Ces données sont importantes pour rassembler afin d'analyser les effets des mutations de la souris sur la voie moléculaire défini des neurones de la sérotonine. De plus, les molécules de guidage qui dirigent ces neurones du raphé 5-HT à différentes cibles ne sont pas connus. Nous avons effectué de nombreuses études sur l'innervation 5-HT visant à détecter la façon dont la partie dorsale et les noyaux du raphé médian sont ciblées sur des régions différentes du cerveau antérieur au cours du développement.Nous avons étudié le rôle de la signalisation ephrinA-EphA dans le ciblage sélectif. Nos résultats démontrent que l'ARNm EphA5 est exprimé sélectivement dans des sous-populations distinctes de neurones du raphé sérotonine. En particulier, EphA5 présentait le plus haut niveau dans les neurones raphé de la sérotonine dorsale (B7). Les résultats des cultures d'explants in vitro et in vivo électroporation analyses indiquent que les ligands de EphA5 (ephrinA5 et ephrinA3) agissent comme des facteurs répulsifs pour les cônes de croissance de l'axone sérotoninergique. Antérograde traçage dans le ephrinA5 - / - souris ont montré des neurones mauvais ciblage du raphé dorsal projections, y compris la projection sérotoninergique. En particulier, notre analyse de tracer les études montrent que le ciblage des dorsales et raphé médian axones à différentes couches du bulbe olfactif est modifié dans le ephrinA5 KO. Cependant, nous ne savons pas à quel stade de développement de ces altérations se produisent, en particulier si cela reflète un changement dans l'orientation des tracts croissant de fibres, ou si cela reflète la maturation de développement en retard quand axones raphé et garantissent des branches dans les régions cibles spécifiques. Nous avons profité d'une nouvelle méthode morphologique, ce qui permet d'analyser l'étiquetage immunocytochimique dans 3_D. 5-HT immunomarquage, dans la projection du cerveau sérotoninergique dans 3_D. Nos résultats montrent que les fibres sérotoninergiques projetant vers le bulbe olfactif besoin d'un calendrier spécial pour entrer la cible. Le profil d'expression de ephrinA5 suggère que ephrinA5 peut être l'un des facteurs qui modulent ce momentIn mice, serotonin (5-HT) midbrain neurons are born from embryonic day 10 to 12, and start extending axons, shortly after neurogenesis, both rostrally to the telencephalon and caudally to the brainstem. These projections are highly collateralized but with some degree of topographic organization. In the telencephalon, the pattern of 5-HT innervation arising from the dorsal (B7, B6) or the medial (B5-B8) nuclei differs. However, there are no systematic detailed developmental studies in mice, which are the most extensively used model, in particular for genetic studies. Such data are important to gather in order to analyze the effects of mouse mutations on defined molecular pathway of serotonin neurons. Moreover the guidance molecules that direct these 5-HT raphe neurons to different targets are not known. We performed several studies of 5-HT innervation aimed at detecting how the dorsal and median raphe nuclei are targeted to different forebrain regions during development. We investigated the role of ephrinA-EphA signaling in selective targeting. Our results demonstrate that EphA5 mRNA is selectively expressed in distinct subpopulation of serotonin raphe neurons. Particularly, EphA5 exhibited the highest level in dorsal raphe serotonin neurons (B7). The results of in vitro explant cultures and in vivo electroporation analyses indicated that the ligands of EphA5 (ephrinA5 and ephrinA3) act as repellent factors for the serotonergic axon growth cones. Anterograde tracing in the ephrinA5 -/- mice showed mistargeting of dorsal raphe neurons projections, including the serotonergic projection. Particularly, our analysis of tracing studies show that targeting of the dorsal and median raphe axons to different layers of the olfactory bulb is altered in the ephrinA5 KO. However we do not know at what developmental stage these alterations occur, in particular whether this reflects an alteration in the orientation of ascending fiber tracts, or whether this reflects late developmental maturation when raphe axons collateralize and branch in specific target regions. We have taken advantage a new morphological method, which allows analyzing immunocytochemical labeling in 3_D. 5-HT immunolabeling, in whole brain serotonergic projection in 3_D. Our findings show that serotonergic fibers projecting to olfactory bulb require a special timing to enter the target. The expression pattern of ephrinA5 suggests that ephrinA5 can be one of the factors that modulate this timing. Overall, our results show for the first time the implication a guidance molecule for the region-specific and time-specific targeting of serotonin raphe neurons and has implications for the anatomo-functional parsing of raphe cell groups
27
Javier, Torrent Míriam. "Role of PS/γ-secretase-mediated signaling during neuronal development and degeneration." Doctoral thesis, Universitat Autònoma de Barcelona, 2018. http://hdl.handle.net/10803/666905.
Full textAbstract:
Presenilina-1 (PS1), el component catalític de γ-secretasa que regula el processament de múltiples proteïnes transmembrana, es troba mutada en la majoria de casos d’Alzheimer familiar (FAD). Evidències recents indiquen que mutacions en PS1 lligades a FAD redueixen el processament de múltiples proteïnes transmembrana, suggerint un mecanisme de pèrdua de funció. De fet, la inactivació de PS1 durant l’embriogènesi comporta defectes morfològics, mentre que la inactivació genètica d’ambdues PS en el cervell adult causa defectes en memòria dependents d’edat i neurodegeneració. A més, la participació de PS en la proteòlisi de molècules de senyalització implicades en el desenvolupament del sistema nerviós, incloent ErbB4, suggereix que aquestes vies de senyalització podrien contribuir a la neurodegeneració.
En aquesta tesi doctoral hem estudiat el paper del processament dependent de PS1/γ‑secretasa d’EphA3 i de la senyalització Nrg1/ErbB4 en el desenvolupament neuronal i la neurodegeneració. Els nostres resultats mostren que PS1/γ-secretasa és necessària pel creixement axonal en el cervell en desenvolupament. PS1/γ-secretasa regula l’elongació axonal a través de l’escissió d’EphA3 en la tirosina 560 que resulta en la generació d’un fragment ICD. EphA3 ICD regula negativament RhoA, interacciona amb la miosina IIA no-muscular (NMIIA) i incrementa la seva fosforilació (S1943) produint el desmuntatge del filament i el creixement axonal. De manera contrària a la senyalització clàssica ephrin-EphA3, la senyalització d’EphA3 dependent de PS/γ-secretasa és independent de lligand. Aquest resultat suggereix per primer cop papers oposats d’EphA3 inhibint (dependent de lligand) o promovent (processament dependent de PS1/γ-secretasa) el creixement axonal en neurones. En segon lloc, mostrem que PS1/γ-secretasa regula l’expressió de Nrg1 tipus III i el processament de Nrg1 tipus III i ErbB4, i regula negativament la sinaptogènesi a través de Nrg1. En conjunt, els nostres resultats mostren que PS1/γ-secretasa regula el creixement axonal i la sinaptogènesi a través de la regulació de la senyalització d’EphA3 independent de lligand i del processament/senyalització de Nrg1/ErbB4, respectivament. La nostra investigació obre el camí a explorar noves relacions entre el neurodesenvolupament i la neurodegeneració, proporcionant evidències sobre l’existència d’una comunicació entre les vies de senyalització implicades en aquests processos.Presenilin-1 (PS1), the catalytic component of γ-secretase that regulates the processing of multiple transmembrane proteins is mutated in the majority of cases of familial Alzheimer’s disease (FAD). Recent evidence indicates that FAD-linked PS1 mutations reduce the γ-secretase cleavage of several transmembrane proteins, suggesting a loss-of-function mechanism. Indeed, PS1 inactivation during embryogenesis leads to morphological defects, whereas genetic inactivation of both PS in the adult brain causes age-dependent memory impairments and neurodegeneration. Moreover, the participation of PS in the proteolysis of signaling molecules involved in the development of nervous system, including ErbB4, suggest that these signaling pathways could contribute to neurodegeneration. In this doctoral thesis we have studied the role of PS1/γ-secretase-dependent cleavage of EphA3 and Nrg1/ErbB4 signaling in neuronal development and neurodegeneration. Our results show that PS1/γ-secretase is required for axon growth in the developing brain. PS1/γ-secretase mediates axon elongation through the cleavage of EphA3 at Tyr560 resulting in the generation of an ICD fragment. EphA3 ICD regulates negatively RhoA, and interacts with and increases phosphorylation (S1943) of non-muscle myosin IIA (NMIIA) leading to filament disassembly and axon growth. In contrast to the classical ephrin/EphA3 signaling, PS/γ-secretase-dependent EphA3 signaling is independent of ligand. This result suggests for the first time opposite roles of EphA3 on inhibiting (ligand-dependent) and enhancing (PS/γ-secretase-dependent processing) axon growth in neurons. Second, we show that PS/γ-secretase regulates Nrg1 type III expression, mediates the processing of Nrg1 type III and ErbB4 and regulates negatively synaptogenesis through Nrg1. Taken together, our results show that PS1/γ-secretase regulates axon growth and synaptogenesis by regulating ligand-independent EphA3 signalling and Nrg1/ErbB4 processing/signalling, respectively. Our investigation paves the way for exploring new relationships between neurodevelopment and neurodegeneration, providing insights of the existence of a crosstalk among the signaling pathways involved in these processes.
28
Glasbrenner, David C. Jr. "Evolution, Expansion, and Functional Divergence of the Commissureless Protein Family." The Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1557143164958451.
Full text
29
Schaeffer, Julia. "The molecular regulation of spinal nerve outgrowth." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/271632.
Full textAbstract:
During amniote embryogenesis, the segmented pattern characteristic of the vertebral column appears early during development through the sequential formation of multipotent structures called somites. Somites differentiate subsequently into dermomyotome (giving rise later to skin and skeletal muscles) and sclerotome (giving rise to vertebral bone structures and cartilage). In addition, sclerotomes subdivide following their rostro-caudal intrasegmental boundary into an axon growth-permissive region (anterior half) and an axon growth-repulsive region (posterior half). This binary system instructs motor and sensory axon navigation, as well as neural crest cell migration, to ensure that the peripheral nervous system develops without obstruction by the future cartilage and bones of the vertebral column. Repellent cues are expressed in posterior half-sclerotomes in order to exclude navigating axons from “no-go” areas and restrict their growth to specific exit points of the future vertebral column. Interestingly, similar repellent cues (e.g. Eph/Ephrins) are expressed in the adult central nervous system (CNS) and have been shown to control connectivity and plasticity throughout life. Following brain or spinal cord injury, these repellent molecules are upregulated by reactive astrocytes accumulating at the lesion site, and may impede axon regeneration in this region. In this dissertation, I am presenting the results of a differential gene expression analysis of anterior and posterior half-sclerotomes, based on RNA-sequencing data and using the chick embryo as a model organism. This study led to the identification of molecules, previously uncharacterized in this system, that may play a role in adhesive and mechanical properties of somites and in axon guidance and fasciculation. I focused on the functional analysis of one molecule of the posterior half-sclerotome, the extracellular matrix protein Fibulin-2. To look at its role in the segmentation of spinal axons, I used ectopic misexpression in a subset of segments based on somite electroporation. The width of spinal nerve bundle growth was restricted by Fibulin-2 overexpression in posterior and anterior half-sclerotomes, suggesting a role in sharpening/controlling the path of spinal axon growth. In addition, I showed that this could occur via an interaction with the axon growth repellent Semaphorin 3A. Then I looked at the expression of Fibulin-2 in two models of CNS injury: mouse cerebral cortical stab injury and rat dorsal crush spinal cord injury. In both cases, I observed an increase in Fibulin-2 protein level compared to control. I also used primary cultures of rat cortical astrocytes to show that the expression of Fibulin-2 after inflammatory cytokine-induced activation is increased. Finally, I studied a candidate axon growth repellent previously identified in the laboratory. I explored the hypothesis that this repellent molecule is an O-glycosylated, spliced variant form of a known protein. To characterize this repellent molecule, I used RNA-sequencing data from chick embryonic somites and 2D gel electrophoresis of an astrocytic cell line protein extract. Together, these results suggested that the developing vertebral column and the adult CNS share molecular features to control axon growth and plasticity. This type of study could lead to the characterization of molecular systems that regulate axon growth, and to the identification of novel therapeutic targets in brain or spinal cord injury.
30
Hayden, Melissa Annette Peifer Mark A. "Novel roles for adenomatous polyposis coli family members and wingless signaling in cell adhesion and axon outgrowth during Drosophila brain development." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2007. http://dc.lib.unc.edu/u?/etd,983.
Full textAbstract:
Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2007.Title from electronic title page (viewed Dec. 18, 2007). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Curriculum of Genetics and Molecular Biology." Discipline: Genetics and Molecular Biology; Department/School: Medicine.
31
Kershner, Leah. "RACK1 regulates point contact formation and local translation in neuronal growth cones." Kent State University / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=kent1524159362714285.
Full text
32
Coats, Charles Jason. "Development of primary neuronal culture of embryonic rabbit dorsal root ganglia for microfluidic chamber analysis of axon mediated neuronal spread of Bovine Herpesvirus type 1." Thesis, Manhattan, Kan. : Kansas State University, 2010. http://hdl.handle.net/2097/4115.
Full text
33
Karali, Kanelina. "Impact of normal ageing and cerebral hypoperfusion on myelinated axons and its relation to the development of Alzheimer's disease." Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/9559.
Full textAbstract:
Cerebral hypoperfusion can occur in normal ageing and is proposed to underlie white matter disturbances observed in the ageing brain. Moreover, cerebral hypoperfusion and white matter attenuation are early events in the progression of Alzheimer’s disease (AD). White matter mostly consists of myelinated axons which have distinct protein architecture, segregated into defined regions; the axon initial segment (AIS), the node of Ranvier, paranode, juxtaparanode, and internode. These sites are essential for action potential initiation and/or propagation and subsequently effective brain function. At the outset of the studies in the thesis there was evidence that the different regions within the myelinated axons are vulnerable to injury and disease. Thus it is hypothesised that in response to normal ageing and/or cerebral hypoperfusion these structures are altered and associated with cognitive impairment and that these effects are exacerbated in a transgenic mouse model (APPSw,Ind, J9 line) which develops age-dependent amyloid-β (Αβ) pathology. The first study aims to investigate the effect of normal ageing and Aβ deposition on myelinated axons and on learning and memory. To address this, the effects of normal ageing on the integrity of the AIS, nodes of Ranvier, myelin, axons, synapses and spatial working memory are examined in young and aged wild-type and TgAPPSw,Ind mice. A significant reduction in the length of nodes of Ranvier is demonstrated in aged wild-type and TgAPPSw,Ind mice. In addition, the length of AIS, is significantly reduced in the aged wild-type animals while the young TgAPPSw,Ind have significantly shorter AIS than the young wild-type mice. These effects are not influenced by the presence of Aβ. Myelin integrity is affected by age but this is more prominent in the wild-type animals whilst axonal integrity is intact. Moreover, there is an age-related decrease of presynaptic boutons only in the TgAPPSw,Ind mice. Contrary to the original hypothesis, working memory performance is not altered with age or influenced by increasing Aβ levels. The second study aims to examine the effects of cerebral hypoperfusion in combination with Αβ pathology and/or ageing on cognitive performance and the structure of myelinated axons. To address this, the effects of surgically induced cerebral hypoperfusion on the integrity of the nodes of Ranvier, paranodes, myelin, axons and spatial working memory performance are investigated in young and aged wild-type and TgAPPSw,Ind mice. A decrease in nodal length is observed in response to hypoperfusion in young and aged animals. This effect is shown to be exacerbated in the young TgAPPSw,Ind animals. Moreover, the disruption of the nodal domain is shown to occur without any gross alterations in myelin and axonal integrity. It is also demonstrated that in response to hypoperfusion, spatial working memory performance is defected in young and aged animals of both genotypes. This deficit is exacerbated in the young TgAPPSw,Ind. The observed changes in the nodal structure are associated with poor working memory performance indicating functional implication for the nodal changes. These data highlight that structures within myelinated axons are vulnerable to ageing and cerebral hypoperfusion. Therefore, the development of strategies that minimize injury or drive repair to these regions is necessary together with therapeutic approaches against the vascular insults that induce hypoperfusion and lead to white matter attenuation and cognitive decline. In the future, it would be interesting to investigate how alterations at the AIS/nodes of Ranvier affect neuronal excitability.
34
Schlüter, Annabelle [Verfasser], and Stephan [Akademischer Betreuer] Frings. "The localization, regulation and function of synaptopodin and the cisternal organelle in the axon initial segment during murine visual system development / Annabelle Schlüter ; Betreuer: Stephan Frings." Heidelberg : Universitätsbibliothek Heidelberg, 2016. http://d-nb.info/1180737849/34.
Full text
35
Hardy, Holly. "Cofilin and drebrin mediated regulation of the neuronal cytoskeleton in development and disease." Thesis, University of Exeter, 2017. http://hdl.handle.net/10871/31746.
Full textAbstract:
The brain is a highly complex structure; neurons extend axons which follow precise paths to make connections with their targets. This extension is guided by a specialised and highly motile structure at the axon tip -the growth cone- which integrates guidance cues to steer the axon through the environment. Aberrant pathfinding is likely to result in developmental impairments causing disruption to brain functions underlying emotion learning and memory. Furthermore, pre-existing connections are constantly remodelled, the ability to do so declines with age, and can have huge impacts on quality of life and well-being. Examining how changes in growth cone behaviour triggered by external cues occurs is crucial for understanding processes in both development and disease. Controlled reorganisation of growth cone cytoskeletal components, such as actin filaments, generate membrane protrusions forming lamellipodia and filopodia. Filopodium formation is commonly associated with sensing the mechanical and chemical environment of the cell. Despite our understanding of the guidance choices that can be made, how filopodia transmit information at a molecular level leading to profound changes in morphology, motility and directionality remains largely unknown. Various actin-binding proteins regulate the number, stability and branching of filopodia. They may therefore have a key role in priming or abrogating the ability of the growth cone to respond to a given guidance cue. I have shown that the actin binding proteins drebrin and cofilin, whilst displaying opposing molecular activities on actin filaments, work synergistically in a temporally regulated manner. A fluorescent membrane marker combined with tagged cofilin and drebrin enabled accurate correlation of cofilin and drebrin dynamics with growth cone morphology and filopodial turnover in live neurons. In contrast to previous in vitro experiments, cofilin was found to enhance the effect of drebrin to promote filopodia formation in intact neurons, and that growth cone spread was significantly constrained when cofilin was knocked down. Importantly, this adds to our understanding of how the two actin binding proteins contribute to directed motility in neuronal growth cone filopodia during guidance. Furthermore, following acute treatment with low concentrations of the repulsive guidance cue semaphorin-3A, neuronal growth cones expressing cofilin displayed increased morphological complexity and filopodial stability. This suggests that traditional collapse signals may serve as pause signals allowing neurons to increase the surface area to sense the environment adequately and enable precise wiring decisions. Remodeling of the cytoskeleton is perturbed in a number of degenerative diseases including Alzheimer's, Huntington's, and Amyotrophic Lateral Sclerosis. These conditions are associated with widespread synaptic loss, resulting in memory loss, cognitive impairment, and movement disorders which leads to severe deterioration in quality of life for those afflicted in addition to wider negative socioeconomic impacts. How widespread synaptic loss occurs is poorly understood. One common characteristic is neuronal stress which can be initiated through different conditions such as neuroinflammation, energetic stress, glutamate excitotoxicity, and accumulation of misfolded proteins, all of which have been associated with perturbation of the actin cytoskeleton and the initiation of the cofilin-actin rod stress response. Dysfunction of the cytoskeleton can lead to the disruption of synaptic activity by blocking the delivery of elements such as organelles and proteins required for maintenance of the synapse. Modulating this stress response offers an approach to protecting the integrity of normal synaptic function. Actin interacting protein-1 is a conserved actin binding protein that enhances the filament disassembly activity of cofilin. I have discovered that AIP-1 has a potent ability to prevent the formation of cofilin rods which are thought to contribute to the neuronal dysfunction in several neurodegenerative disorders, even when they are treated with amyloid-β or subjected to metabolic stress. This is the first study to demonstrate a molecular mechanism for preventing rod formation in the presence of a neuronal stressor and has the potential to protect against rod formation by other stressors associated with disease such as inflammation and excitotoxicity. AIP-1 offers the exciting possibility of a means to reverse cofilin rod formation and the subsequent cytoskeletal pathology associated with dementia and has potential for therapeutic exploitation in human disease. Furthermore, it is the first study to demonstrate that AIP-1 localises to areas of rapid actin remodeling in neuronal growth cones. Exploiting the action of AIP-1 therefore represents an exciting and novel therapeutic avenue to tackle neurodegeneration.
36
Davey, John William. "Identification of b-catenin and other RNAs in developing thalamic axons." Thesis, University of Edinburgh, 2009. http://hdl.handle.net/1842/4011.
Full textAbstract:
This thesis provides evidence for the presence of multiple RNAs in the axons and growth cones of developing thalamic cells, particularly the mRNA for the cell adhesion and Wnt-signalling-related molecule b-catenin. After many decades of effort, mRNAs have been shown to be present in the axons of many different systems in recent years. Furthermore, these mRNAs have been shown to be locally translated at the growth cone, and this local translation is required for axons to turn in response to multiple guidance cues. As studies accumulate, it is becoming clear that different axonal systems contain different complements of mRNAs and have different requirements for local translation. One axonal system which has not been investigated to date is the thalamocortical tract. The nuclei of the thalamus are connected to the areas of the cortex via bundles of axons which travel from the thalamus to the cortex via the ventral telencephalon during embyronic development. These axons make a number of turns and are guided by many cues and other axonal tracts before innervating their cortical target. In this thesis, a quantitative real-time polymerase chain reaction (qRT-PCR) approach is developed to isolate multiple mRNAs from developing thalamic axons in vitro, including b-catenin mRNA, b-actin mRNA, 18S ribosomal RNA and ten other mRNAs. The method used should be suitable for use with other axonal systems and also for testing the effect of guidance cues on mRNA expression in axons. The qRT-PCR results for b-catenin, b-actin and 18S have been validated using in situ hybridisation. Analysis of in situ hybridisation results indicates that b-catenin and 18S, but not b-actin, are upregulated in the growth cone compared to the axon. As b-catenin has been shown to be involved in axon guidance via Slit and ephrin guidance cues in other axonal systems, and these guidance cues act upon thalamocortical axons, the identification of b-catenin mRNA in thalamic axons is an important step towards a full understanding of the thalamocortical system. The results presented here indicate that local protein synthesis is likely to occur in thalamic axons as it does in other axonal systems, and that local translation is likely to be important for thalamic axonal responses to guidance cues and other axonal tracts.
37
McCormick, Aleesha Marie. "Development and Implementation of Multi-Cued Guidance Strategies for Axonal Regeneration." University of Akron / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=akron1417449988.
Full text
38
Borowski, Peter. "Stochastic dynamics in olfactory signal transduction and development." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2006. http://nbn-resolving.de/urn:nbn:de:swb:14-1159519135136-22697.
Full textAbstract:
The purpose of the senses of animals (and humans) is to translate information available in the external environment into internal information that can be processed by the brain. In the case of the olfactory sense -- the sense of smell -- this is information about the type and concentration of odourants. In the last 15 years major progress has been made in the experimental understanding of the first two stages of the olfactory sense: the signal transduction inside the cilia of the olfactory receptor neurons and the first 'relay station' in the brain, the olfactory bulb, as well as the connection between these two. Theoretical studies that classify the experimentally achieved knowledge or help in testing different biological hypotheses are only starting to be developed. The present work aims to contribute to the theoretical understanding of the first two stages of the olfactory sense. The first processing of the olfactory information, the olfactory signal transduction, is accomplished by a complex chemical network in the sensory cells with the task of coding the available information reliably over a wide range of stimulus strength. In the present work, methods from nonlinear dynamics combined with network theory (namely stoichiometric network analysis) are used to identify a specific negative feedback mechanism that accounts for a number of recently measured experimental results, e.g. oscillations in calcium concentration or the adaptation of the cell towards strong stimuli. This feedback is an experimentally well-established inhibition of cationic channels by the calcium-loaded form of the protein calmodulin. The results of the set of coupled nonlinear deterministic differential equations describing these dynamics agree quantitatively with experimental data. A bifurcation analysis of the system considered shows the robustness of the oscillatory solution against changes in parameters used. It also gives predictions that could serve as an experimental test of the proposed mechanism. Further abstraction and simplification of this specific signal transduction unit leads to a stochastic two-level system with negative feedback, that can not only be found in signalling systems but also in other branches of cell biology, e.g. regulated enzyme activity or in transcription dynamics. Whereas the description outlined above is fully deterministic, here the model system is intrinsically noisy. The influence of the feedback on the intrinsic noise as well as on the signalling properties of the module are analysed in detail by computing mean values, correlation and response functions of the two dynamical system variables using different analytical approaches. Common to all of them is that the intrinsic noise of the system is calculated from its dynamics rather than being introduced by hand. A master equation is used to get generally valid expressions for the mean values. Correlation and response functions for weak feedback are calculated within a path-integral description, and an easier self-consistent method with restricted validity is developed for future extensions of the module such as, e.g., the inclusion of diffusion. The results of the analytical methods are compared to each other and to the results of extended numerical simulations. The considered quantities allow for statements regarding the quality of the signal transduction properties of this module and the positive and negative effects of feedback on it. Going one step up in the information processing in the olfactory sense, another system is found that shows interesting dynamics during development and is influenced by stochastic effects: the formation of the neural map on the surface of the olfactory bulb -- stage two in the olfactory system. The dynamics of this very complex biological pattern formation process is studied mostly numerically focusing on three different aspects of axonal growth. Possible chemical guidance cues and the reaction of axonal growth cones to them are described using different levels of detail. There is strong experimental evidence for interactions among growing axons which is implemented in different ways into models. Finally, axon turnover is considered and used in the most promising simulation approach, where many axons grow as interacting directed random walkers. For each of these aspects, qualitative features of respective experiments are reproducedDie Sinne der Tiere (und Menschen) dienen dazu, Informationen über die Aussenwelt in neuronale, ' interne' Information zu 'übersetzen'. Im Falle des Geruchssinns sind dies Informationen über die Art und Konzentration von Geruchsstoffen. In den letzten 15 Jahren wurden grosse Fortschritte im experimentellen Verständnis der ersten beiden Stufen des Geruchssinns gemacht, sowohl was die Signaltransduktion in den Zilien der Geruchszellen betrifft, als auch bezüglich der ersten 'Schaltstelle' im Gehirn, dem olfaktorischen Bulbus (sowie in der Verbindung dieser beiden Stufen). Die Entwicklung theoretischer Studien, die die experimentell gewonnenen Daten klassifizieren können, befindet sich dagegen erst am Anfang. Ziel der vorliegenden Arbeit ist es, zum theoretischen Verständnis dieser ersten beiden Stufen beizutragen. Die erste Verarbeitung der olfaktorischen Information, die olfaktorische Signaltransduktion, wird durch ein komplexes chemisches Netzwerk in den Sinneszellen bewerkstelligt. In dieser Dissertation werden Methoden der nichtlinearen Dynamik, kombiniert mit Netzwerktheorie (stöchiometrische Netzwerkanalyse) benutzt, um einen negativen Rückkopplungsmechanismus zu identifizieren, der einige in neuerer Zeit gewonnene experimentelle Ergebnisse erklären kann, u.a. Oszillationen der Kalziumkonzentration oder die Anpassung der Zelle an starke Reize. Bei dieser Rückkopplung handelt es sich um eine experimentell gut bestätigte Hemmung eines Kationenkanals durch den Kalziumkomplex des Proteins Calmodulin. Das Ergebnis der vier gekoppelten nichtlinearen deterministischen Differenzialgleichungen, die das dynamische Verhalten des Systems beschreiben, stimmt quantitativ mit experimentellen Daten überein. Eine Bifurkationsanalyse zeigt die Robustheit der oszillierenden Lösung gegenüber Veränderungen der verwendeten Parameter und macht Vorhersagen möglich, die als experimentelle Tests des vorgeschlagenen Mechanismus dienen können. Eine weitere Abstrahierung der oben beschriebenen Signaltransduktionseinheit führt zu einem stochastischen Zweiniveausystem mit negativer Rückkopplung, das nicht nur in Signalsystemen gefunden werden kann, sondern auch in anderen Bereichen der Zellbiologie. Im Gegensatz zu der oben beschriebenen, komplett deterministischen Beschreibung zeigt das hier betrachtete Modellsystem intrinsisches Rauschen. Der Einfluss der Rückkopplung auf das Rauschen sowie auf die Signalübertragungseigenschaften des Moduls werden detailliert analysiert, indem mit Hilfe verschiedener analytischer Methoden Mittelwerte, Korrelations- und Antwortfunktionen des Systems ausgerechnet werden. Diese Methoden habe alle gemein, dass das intrinsische Rauschen des Systems aus der Dynamik selbst berechnet wird und nicht ' von Hand' eingefügt wird. Um allgemeingültige Ausdrücke für die Mittelwerte zu bekommen, wird eine Mastergleichung aufgestellt und gelöst. Die Korrelations- und Antwortfunktionen werden für schwache Rückkopplung mit Hilfe einer Pfadintegralmethode ausgerechnet, und eine einfachere, selbstkonsistente Methode begrenzter Gültigkeit wird für mögliche Erweiterungen des Systems, z.B. die Berücksichtigung von Diffusion, entwickelt. Die Ergebnisse der verschiedenen analytischen Methoden werden miteinander und mit den Ergebnissen ausführlicher numerischer Simulationen verglichen. Die betrachteten Grössen ermöglichen Aussagen über die Qualität der Signaltransduktion dieses Moduls sowie über die positiven und negativen Effekte der Rückkopplung auf diese. Ein weiteres Beispiel für interessante und von stochastischen Effekten beeinflusste Dynamik findet man einen Schritt weiter in der olfaktorischen Signalverarbeitung: Die während der Entwicklung stattfindende Ausbildung der neuronalen Karte auf der Oberfläche des olfaktorischen Bulbus, der zweiten Stufe des olfaktorischen Systems. Die Dynamik dieser sehr komplexen biologischen Musterbildung wird mittels numerischer Simulationen untersucht, wobei der Schwerpunkt auf drei verschiedene Aspekte axonalen Wachstums gesetzt wird. Die Reaktion axonaler Wachstumskegel auf mögliche chemische Signalstoffe wird verschieden detailliert beschrieben. Es gibt deutliche experimentelle Hinweise auf Wechselwirkung zwischen Axonen, was in den Modellen auf verschiedene Arten implementiert wird. Schliesslich wird die Erneuerung der Axone betrachtet und im vielversprechendsten Modell, in dem viele Axone als wechselwirkende gerichtete random walkers simuliert werden, berücksichtigt und analysiert. Für jeden dieser drei Aspekte können entsprechende experimentelle Ergebnisse qualitativ reproduziert werden
39
Steup, Andreas. "Expression und Funktion neuronaler Leitmoleküle im Hippokampus." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2001. http://dx.doi.org/10.18452/14722.
Full textAbstract:
Die Semaphorine Sema3A und Sema3C sowie Netrin-1 und deren Rezeptoren, die Neuropiline und DCC wurden in der vorliegenden Arbeit hinsichtlich ihrer Expression und auf ihre funktionellen Eigenschaften bezüglich des Auswachsens von Axonen, die die intrinsischen und afferenten hippokampalen Projektionen bilden, untersucht. Während die Expressionsmuster von Sema3A schon gut bekannt waren, wurde in der hier vorliegenden Arbeit die Expression des Rezeptors von Sema3A, Neuropilin-1 (NP-1), untersucht. NP-1 wird von Embryonaltag E17 an im entorhinalen Kortex, dem Subiculum und der hippokampalen Anlage exprimiert. Es konnte eine starke postnatale Expression von NP-1 in der CA3-Region und eine schwächere Expression in der CA1-Region, dem Gyrus dentatus und dem entorhinalen Kortex gezeigt werden. Außerdem wurden in dieser Arbeit die Expressionsmuster von Sema3C und Neuropilin-2 (NP-2) genauer analysiert. Etwa zum Zeitpunkt der Geburt (P0) wurde Sema3C im Gyrus dentatus und in der Cornu ammonis Region exprimiert. Der Sema3C-Rezeptor Neuropilin-2 wurde zu diesem Zeitpunkt ebenso im Gyrus dentatus und CA3-Region, schwächer auch in der CA1-Region exprimiert. Es wurde keine Expression dieser beiden Faktoren im entorhinalen Kortex detektiert. In Kokulturstudien zwischen mit Sema3A bzw. Sema3C transfizierten Zellaggregaten und Explantaten aus den hippokampalen Subregionen wurden für spezifische Explantate ein funktioneller Zusammenhang zwischen der Sekretion der Semaphorine und dem Auswachsen der jeweiligen Explantate in einer drei-dimensionalen Kollagenmatrix deutlich. Sema3A besitzt repulsive Eigenschaften auf Explantate vom Gyrus dentatus, der CA1- und der CA3-Region sowie dem entorhinalen Kortex. Die Interaktion zwischen Sema3A und NP1 beeinflußt das Einwachsen bzw. die Terminierung entorhinaler Fasern in der Molekularschicht des Gyrus dentatus, indem Sema3A eine repulsive Barriere für einwachsende Fasern und Moosfasern, die in Richtung der CA3-Region auswachsen, darstellt. Sema3C besitzt repulsive Eigenschaften auf Fasern des medialen Septums und beeinflußt dadurch das Einwachsen dieser Fasern entlang der Cornu ammonis Region in den Hippokampus. Weiterhin wurden in dieser Arbeit die Expressionsmuster von Netrin-1 und DCC im Hippokampus sowie die funktionellen Eigenschaften von Netrin-1 untersucht. Netrin-1 wird bereits zum Zeitpunkt E17 im Neokortex exprimiert, konnte im Hippokampus jedoch erst ab dem postnatalen Entwicklungsstadium P1 detektiert werden. Während im Gyrus dentatus nur ein schwaches und im entorhinalen Kortex kein Signal gefunden werden konnte, wird Netrin-1 stark in der Cornu ammonis Region exprimiert. Der Rezeptor DCC wird dagegen schon früher in der Embryonalentwicklung, ab E15, diffus in der hippokampalen Anlage exprimiert. Ab P1 lassen sich diese Signale im Gyrus dentatus und in den CA1-CA3-Regionen unterscheiden. Von den untersuchten Explantaten der hippokampalen Region zeigte Netrin-1 nur auf die Fasern von Gyrus dentatus und CA3, welche die hippokampale Kommissur bilden, einen attraktiven Wachstumseffekt. Dies bestätigt Befunde aus Netrin-1- und DCC-defizienten Tieren, in denen die hippokampale Kommissur aufgrund des fehlenden axonalen Leitmoleküls bzw. seines Rezeptors nicht ausgebildet wird.In this work, the semaphorins Sema3A and Sema3C as well as Netrin-1 and their receptors, the neuropilins and DCC, were investigated regarding their expression and functional properties on outgrowing axons, which are forming the intrinsic and afferent hippocampal projections. Because of the already well known expression patterns of Sema3A, this work focused on the expression of the receptor of Sema3A, NP-1. From embryonic stage E17 on, NP-1 is expressed in the entorhinal cortex, the subiculum and the hippocampal Anlage. A strong postnatal expression of NP-1 in the CA3-region could be detected, while the expression pattern in the CA1-region, the dentate gyrus and the entorhinal cortex was weaker. Additionally, the expression patterns of Sema3C and NP-2 were investigated in greater detail. At birth (P0), Sema3C was expressed in the dentate gyrus and the cornu ammonis region. The expression of its receptor NP-2 could be detected at the same timepoint P0 in the dentate gyrus and the CA3-region and, less pronounced, in the CA1-region.There could not be detected any expression of Sema3C or NP-2 in the entorhinal cortex. In functional coculture studies between with Sema3A or Sema3C transfected cell clusters and neuronal explants from subregions of the hippocampal formation, these factors were investigated for their influence on axonal outgrowth within a three-dimensional collagen gel matrix. Sema3A has repulsive properties on explants from the dentate gyrus, the CA1- and CA3- regions and the entorhinal cortex. I the resulting model, the interaction between Sema3A and NP-1 influences the ingrowth and/or the termination of entorhinal fibers into the molecular layer of the dentate gyrus by a repulsive barrier formed by Sema3A. The same barrier also acts on mossy fibers to allow them to grow only in direction of the CA3-region. Sema3C has repulsive properties on fibers from the medial septum and shapes the ingrowth of these fibers along the cornu ammonis region into the hippocampus. Additionally, the expression patterns of Netrin-1 and DCC and their functional properties in the hippocampus were investigated. Netrin-1 is already expressed in the cortex at E17, although the onset of expression in the hippocampus is at P1. In the dentate gyrus, a weak signal could be detected, but no signal was found in the entorhinal cortex. In the cornu ammonis region, however, Netrin-1 showed a strong expression signal. The Netrin-1 receptor DCC could be detected as early as E15 with a diffuse distribution in the hippocampal Anlage. From P1 on, these signals could be distinguished in the dentate gyrus and the CA1-CA3-regions. Netrin-1 showed attractive properties only on fibers from explants of the dentate gyrus and the CA3-region, which form the hippocampal commissure. These results confirm previous findings from Netrin-1 and DCC deficient animals in which the absence of the hippocampal commissure was described.
40
Charoy, Camille. "Mécanismes moléculaires de polarisation des projections neuronales dans l'axe droite-gauche." Thesis, Lyon 1, 2014. http://www.theses.fr/2014LYO10090/document.
Full textAbstract:
Les circuits nerveux s'organisent autour des grands axes de polarité du corps. Au cours du développement, la navigation ainsi que l'arrangement spatial des projections au sein de leurs territoires cibles sont contrôlés par de nombreux facteurs de guidage. Pendant ma thèse je me suis intéressée à deux modèles de formation des circuits neuronaux présentant une polarité dans l'axe droite-gauche. Le premier concerne la mise en place des projections des interneurones commissuraux de la moelle épinière, un modèle de navigation orientée et le second, porte sur l'innervation des motoneurones phréniques, un modèle d'organisation asymétrique dans le territoire cible. Les mouvements comme la marche, la course ou la nage font intervenir des circuits neuronaux particuliers dédiés à la coordination des deux côtés du corps. Ces circuits sont formés majoritairement par les projections des interneurones commissuraux de la moelle épinière. Au cours du développement, ces interneurones élaborent un axone qui traverse la ligne médiane partageant les deux moitiés du système nerveux central pour se connecter aux motoneurones ou à d'autres interneurones de l'hémi-moelle opposée. De nombreux travaux ont porté sur les mécanismes de traversée de la ligne médiane et ont mis en évidence un rôle fondamental de facteurs de guidage comme la Nétrine, les Slit et les Sémaphorines. Ces molécules sont secrétées par les cellules de la plaque du plancher (PP) environnant la ligne médiane ventrale. Lors de leur traversée les axones commissuraux sont tout d'abord attirés par les signaux attractifs secrétés par les cellules de la PP. Une fois que les axones ont traversé la ligne médiane, ils perdent leur sensibilité aux facteurs attractifs et développent des nouvelles sensibilités pour des facteurs répulsifs qui les guident hors de la PP. Une étude menée par mon équipe a permis de montrer que les axones commissuraux acquièrent une réponse à la Sémaphorine3B seulement après avoir traversé la ligne médiane. Dans cette étude, l'équipe a montré que pendant la phase qui précède la traversée de la PP, une protéase, la Calpaine-1, dégrade la Plexine-A1, le corécepteur de Sema3B (Nawabi et al., 2010). L'inhibition de cette voie pendant la traversée de la PP conduit à la stabilisation de la PlexineA1 à la surface du cône de croissance et la formation d'un complexe récepteur de Sema3B fonctionnel composé de la Plexine-A1 et de la sous-unité de liaison de Sema3B, la Neuropiline2. La suppression de l'activité Calpaine est contrôlée par des signaux de la PP dont la nature n'était pas connue. Au cours de ma thèse j'ai identifié et caractérisé les contributions fonctionnelles de deux signaux de la PP qui sont responsables de la suppression de l'activité Calpaine et la sensibilisation des axones à Sema3B après la traversée. Ces résultats ont permis d'élargir les fonctions du facteur neurotrophique gdnf, et d'apporter de nouveaux éléments sur les voies de contrôle de la signalisation Sémaphorine, les processus de traversée et les modulations post-traductionnelles des récepteurs Plexines. Dans un deuxième projet, je me suis intéressée aux asymétries droite-gauche du système nerveux, par l'étude d'un nouvel exemple de circuit neuronal asymétrique : l'innervation motrice du diaphragme. Le diaphragme est un muscle indispensable à la respiration, il est composé d'une région centrale tendineuse et de deux muscles latéraux. Ces muscles sont innervés par un groupe particulier de motoneurones provenant de la moelle épinière cervicale, qui forment les nerfs phréniques droits (D) et gauches (G). Malgré une position centrale dans l'organisme et une morphologie apparente symétrique, nous avons découvert que le diaphragme présente une asymétrie musculaire ainsi qu'une asymétrie nerveuse. Etonnamment les motoneurones phréniques établissent un motif de connexion typique et différent sur les muscles droit et gauche du diaphragme [etc...]The nervous circuits have stereotype positions within the major body axes. During development, axonal navigation and special positioning of the axon tracts in the target territories are regulated by many axon guidance factors. During my thesis I have been interested in two models of neuronal circuit formation that present a leftright polarity. The first one concerns the formation of the spinal commissural neurons projections, a model of oriented navigation along the left-right axis and the second one is the innervation of the phrenic motoneurons, a novel model of left-right asymmetric innervation pattern. Rhythmic locomotor movements like walking, running or swimming require neuronal circuits ensuring left-right coordination. Central components of these circuits are commissural neurons of the spinal cord. During development theses neurons are projecting axons across the midline that divides the nervous system in two parts, which connect the contralateral side of the spinal cord. Extensive work focused on the mechanisms controlling midline crossing. These study revealed a fundamental role of guidance factors secreted by floor plate cells at the ventral midline such as Netrins, Slits and Semaphorins. They also revealed that before crossing, axons are attracted towards the floor plate, and navigating by the floor plate they lose responsiveness to these attractive factors and develop a new sensitivity to repulsive cues that drive them out of the floor plate. In a previous study, my team showed that commissural axons gain response to Sema3B only after floor plate crossing (Nawabi et al., 2010). Before crossing, Plexin-A1 the Sema3B receptor is processed by a protease: the Calpain1. During crossing suppression of this pathway enable Plexin-A1 expression at growth cone surface, leading to sensitization to Sema3B. The suppression of Calpain activity was found controlled by floor plate signals, which remained unknown. During my thesis I have identified and characterized the functional contribution of two floor plate signals that are responsible for the inhibition of Calpain activity and axon sensitization to Sema3B after midline crossing: the neurotrophic factor gdnf and the cell adhesion molecule NrCAM. My results bring new elements on the control of midline crossing processes, Semaphorin signaling, and post-translational modifications of the Plexins receptors. In my second project, I have been interested in left-right asymmetries of the nervous system through the study of a new model of left-right asymmetry: the diaphragm innervation. The diaphragm is a muscle essential for breathing, it is composed of one central tendinous region and two lateral muscles. These muscles are innervated by a subset of cervical spinal cord motoneurons which forms the left and right phrenic nerves. Despite its central disposition in the organism and its apparent symmetry, we noticed that the diaphragm presents nervous and muscular asymmetries. Surprisingly phrenic motoneurons present typical and different nerve patterns on the left and right diaphragm muscles. Diverse left-right characteristic have been documented in the brain but none concerned yet the spinal cord or peripheral projections. My thesis work has been dedicated to the identification of the mechanisms that control the asymmetry of the diaphragm innervation. My work showed that this asymmetry is set up very early during development via a molecular pathway that is known to control the visceral organ asymmetry. This work opens numerous perspectives and brings new information on the molecular diversity of spinal neurons that could shed a new light on the mechanisms of motoneuron physiopathology
41
Purdy, Ashley Morgan. "Roles of Planar Cell Polarity Proteins in CoPA Axon Pathfinding." VCU Scholars Compass, 2016. http://scholarscompass.vcu.edu/etd/4289.
Full textAbstract:
In zebrafish, CoPA (Commissural Primary Ascending) is the first among ascending commissural axons to pathfind anteriorly and form the spinal commissure. One pathway that guides their anterior growth is the planar cell polarity (PCP) signaling pathway, but it is not fully known how PCP signaling regulates anterior guidance. We examined CoPA pathfinding in various PCP mutants to determine if anterior-posterior (A-P) guidance of CoPAs is dependent on PCP signaling. We found that certain PCP mutants exhibited anterior pathfinding defects, with approximately half of all affected CoPAs migrating incorrectly posteriorly. By using a translation-blocking DCC (Deleted in Colorectal Cancer) morpholino to prevent CoPA midline crossing, we discovered that CoPA axons in Fzd3a and Scribble mutants show severe defects in A-P guidance, which suggest that PCP influences A-P guidance of CoPAs prior to and after midline crossing.
42
George, Nicholas M. "Resolution of Inflammation Rescues Axon Initial Segment Disruption." VCU Scholars Compass, 2016. http://scholarscompass.vcu.edu/etd/4186.
Full textAbstract:
Axonal domains are required for proper neuron function. These domains are unstable and degenerate concurrent with the inflammation in multiple sclerosis (MS) and the inflammatory disease models experimental autoimmune encephalomyelitis (EAE) and lipopolysaccharide (LPS) induced inflammation. Previous studies from our laboratory have shown that the axon initial segment (AIS) is maintained independently of the presence of myelin, but that AIS disruption is seen in MS as well as EAE and LPS-mediated inflammation. AIS loss can be interrupted in the early stage of EAE using the anti-inflammatory drug Didox. However, the potential for Didox directed repair of the AIS in later stages of disease has not been investigated. Here, we utilize two models of CNS inflammation to assess the possibility of reversing AIS pathology. Based on our findings, we present the first evidence that AIS degeneration, an axonal pathology observed in MS and in chronic inflammation, is reversible.
43
Godfrey, Grayland W. II. "Characterizing the Role of Key Planar Cell Polarity Pathway Components in Axon Guidance." VCU Scholars Compass, 2017. http://scholarscompass.vcu.edu/etd/4841.
Full textAbstract:
An essential process to the development of the neural network of the nervous system is axon guidance. The noncanonical Wnt/Planar Cell Polarity pathway has been identified as an integral component in controlling the projection of axons during axon guidance. Prickle, ROR1 and ROR2 are PCP related proteins that do not have clearly defined roles in the process. This study aims to use zebrafish CoPA neurons as a model to study the roles of Prickle, ROR1, and ROR2 in axon guidance. Using in situ hybridization, morpholino knockdown, and CRISPR/Cas9 loss of function experiments were able to identify ror1, ror2 and prickle as potential required components in CoPA neuron axon guidance. Elucidating the role of these protein in axon guidance not only will increase our knowledge of the PCP pathway but it will also increase our understanding of the development of the nervous system.
44
Chung, Kit Ying. "Developmental mechanisms that regulate axon routing in the retinofugal pathway of mouse embryos." Thesis, University of Oxford, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.400083.
Full text
45
Guibal, Christophe Rene Charles. "Organization and development of mammalian retinal ganglion cell axons." Thesis, City University London, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.446267.
Full text
46
Mather, Nicole K. "The development of the major brainstem decussations." Thesis, University of Oxford, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.365330.
Full text
47
Schneider, Patricia Neiva Coelho. "Role for the Axin-RGS domain during embryonic development: maternal vs. zygotic functions." Diss., University of Iowa, 2010. https://ir.uiowa.edu/etd/598.
Full textAbstract:
Upon sperm entry, the vertebrate egg undergoes a series of cell divisions that create a number of smaller cells without increasing the embryonic mass. This induces an elevation of intracellular calcium transient that is conserved across species. In zebrafish, fertilization occurs through an opening in the chorion, the micropyle and in Xenopus it can occur anywhere in the animal hemisphere. Wnt signaling activation is required during dorsal-ventral axis specification and it needs to be suppressed during the regionalization of the brain. Axin is a negative regulator of Wnt signaling and contains an RGS (Regulator of G Protein Signaling) domain. RGS domains are typical of RGS proteins, which are involved in a distinct signaling pathway, G-protein signaling. RGS proteins exert a negative effect of G-protein signaling by accelerating the GTPase activity (GAP) of the Gα subunit, thus turning off the signaling. Axin contains an RGS domain, however, it is not clear whether Axin is directly involved in G-protein signaling. We will also present a work performed using another negative regulator of the Wnt signaling network called naked cuticle (Nkd). Nkd has been shown to modulate β-catenin dependent and independent Wnt signaling. In chapter 2, we will show that the Axin-RGS like function is dispensable during the formation of the dorsal-ventral axis. We manipulated this protein by creating a point mutation in a critical aminoacid within the Axin-RGS domain, known to be detrimental for the GAP function of RGS proteins, Axin1Q162A. Maternal depletion of Axin1 in Xenopus oocytes causes hyperactivation of Wnt signaling and results in dorsalization. Axin1Q162A is able to suppress the dorsalization of maternally depleted embryo and restore normal dorsa-ventral axis formation.
In chapter 3, we will describe the role of Axin during the patterning of the vertebrate brain. We show that the point mutant is not able to restore normal brain development in zebrafish embryos after Axin knockdown. We hypothesize that Axin-RGS like function is necessary during the patterning of the vertebrate brain that occurs after zygotic transcription has been initiated. Moreover, we show that Axin-RGS like activity may be dispensable during this stage of development. Finally, we demonstrate that Axin1Q162A localization differs from the wildtype Axin1 and Axin1 but not Axin1Q162A is localized to the plasma membrane upon Gα overexpression in zebrafish embryos.
Embryonic organ laterality is preceded by molecular and physiological asymmetries. In chapter 4 we describe the role of another Wnt antagonis, Nkd cuticle, during left-right patterning. Prior to organogenesis, a group of cells called Dorsal Forerunner Cells, (DFCs), migrate ahead of the dorsal blastoderm during gastrulation to form the Kupffer's vesicle (KV). This vesicle will trigger a signaling cascade that will culminate with left-right determination. We show data that support the requirement of Nkd in organ laterality and convergence and extension movements using zebrafish and Xenopus laevis.
48
Nawabi, Homaira. "Guidage axonal commissural : mécanismes de sensibilisation au signal de la ligne médiane Sémaphorine 3B." Thesis, Lyon 1, 2009. http://www.theses.fr/2009LYO10305.
Full textAbstract:
Les mouvements locomoteurs rythmiques nécessitent l’intervention de circuits neuronaux qui coordonnent l’activité motrice des deux parties du corps. Ces circuits sont formés majoritairement par les projections des interneurones commissuraux de la moelle épinière. Des facteurs de guidage comme la Nétrine, les Slits jouent un rôle fondamental dans la mise en place de ces projections. Une étude a également montré qu’une signalisation impliquant le récepteur Neuropiline2 (Nrp2) des signaux Sémaphorines de la classe 3 (Sema3), participe au guidage de ces projections et cela uniquement après la traversée de la ligne médiane (Zou et al. 2000). Ma thèse porte sur l’étude fonctionnelle d’un ligand de la Nrp2, la Sema3B dans le développement de ce système de projections. J’ai analysé une souris invalidée pour Sema3B et observé de nombreuses erreurs de trajectoires après la traversée de la ligne médiane. Je me suis ensuite intéressée aux mécanismes sous-jacents au gain de réponse : par une approche pharmacologique et biochimique j’ai pu montrer que le signal de la plaque du plancher inhibe une activité de dégradation dépendante de la calpaine1. L’inhibition de cette voie conduit à la stabilisation d’un co-récepteur de la Nrp2, la Plexine A1 dont l’expression est très faible dans les axones n’ayant pas encore traversé la ligne médiane. Cette régulation permet alors l’assemblage d’un complexe récepteur fonctionnel de Sema3B, comprenant cette Plexine associée à la Nrp2 au niveau des cônes de croissance. J’ai identifié la molécule d’adhérence NrCAM, et le facteur neurotrophique GDNF comme étant les facteurs de la plaque du plancher déclencheurs de la réponseRhythmic locomotor movements require neuronal circuits ensuring left-right coordination. Spinal commissural projections participate to left-right coordination of limb movements by mediating reciprocal inhibition in synchrony. Extensive research of the mechanisms governing the formation of commissural pathways focused on dorsally-located spinal commissural neurons, establishing a fundamental role for multiple guidance cues derived for the midline and surrounding tissues, including Netrins, Slits and various morphogens. Semaphorin (Sema2)/Neuropilin-2 (Nrp2) signaling has been proposed to contribute to the guidance of commissural projections in the spinal cord at the post- but not pre-crossing stage (Zou et al, 2000). My PhD project aimed at analyzing the role of a Nrp2 ligand, Sema3B, in the guidance of spinal commissural projections, whose expression is dynamic and restricted to some territories, including the floor plate in which axons cross the midline. Analysis of Sema3B null mice showed that the loss of Sema3B induces a range of guidance defects of post-crossing commissural pathways. I investigated the underlying mechanisms and found that the floor plate signal induces through blockade of a calpain 1-dependant pathway the stabilization of the Nrp2 co-receptor Plexin-A1, and enable the assembly of Nrp2/Plexin-A1 sub-units into functional complexes for Sema3B in post-crossing commissural growth cones. I identified the cell adhesion molecule NrCAM and the neurotrophic factor GDNF as being the floor-platederived signals triggering the gain of response
49
Offergeld, Anika. "Acute effects of Axin loss in the mouse liver and embryonic development." Thesis, Cardiff University, 2015. http://orca.cf.ac.uk/84458/.
Full textAbstract:
Hepatocellular carcinomas carrying Axin1 mutations belong to a subset of tumours with an especially poor prognosis. Data obtained from an Axin1 mutant mouse line, challenged the traditional idea of Axin function; as simply a component of the β-Catenin-destruction complex. Axin1 deletion led to the development of highly proliferative HCC in the absence of an obvious Wnt/β-Catenin signature. In order to uncover the mechanism(s) leading to Axin dependent tumourigenesis, this study focused on the role of Axin in two systems. Firstly, we generated an allelic series of Axin mutant ES cell lines to analyse the role of Axin1 and 2 in ES cells. We could show, that single Axin mutants had a largely normal ES cell phenotype. In Axin double mutant ES cells, Wnt target gene expression was slightly upregulated, but cell proliferation stayed at normal levels. By contrast, upon differentiation into embryoid bodies, multiple readouts of the Wnt pathway were increased and a G2/M and cell cycle related gene expression profile was activated, accompanied by severe differentiation defects. In the second system, we developed Axin1 mutant 3D liver cultures, which allow fate tracing of Axin mutant and wt cells in real time. We could show tightly regulatable gene deletion in vitro and produced preliminary evidence that Axin1 loss in culture closely mimics the in vivo situation in respect to G2/M gene expression in the absence of Wnt activation. Overall, the effects of Axin loss on Wnt signalling and cell cycle regulation appeared to be tissue and cell cycle specific. Future use of the 3D culture system, together with the data obtained in Axin mutant ES cells and embryoid bodies, will not only advance our understanding of the involvement of Axin1 in hepatocellular carcinogenesis and cell cycle regulation; but may also be the starting point in the development of new therapeutic strategies.
50
Ros, i. Torres Oriol. "Paper de les Proteïnes Sinàptiques i l'Exocitosi en els processos de Guia Axonal i Migració." Doctoral thesis, Universitat de Barcelona, 2013. http://hdl.handle.net/10803/120452.
Full textAbstract:
La guia axonal i la migració són dos processos similars i crucials per al desenvolupament. Aquests dos elements permeten el correcte posicionament cel•lular i la selecció de dianes essencial per a la funcionalitat posterior del sistema nerviós central, i es fonamenten en la regulació de l’avanç del con de creixement o la cèl•lula, respectivament, en resposta a estímuls externs, quimioatraients i quimiorepulsius, proporcionats per molècules de guia.
Un altre component clau del funcionament neuronal és l’exocitosi, que permet la propagació dels estímuls nerviosos entre cèl•lules a través de la fusió de vesícules amb la membrana plasmàtica i l’alliberament de neurotransmissors. L’exocitosi està vehiculada per les proteïnes SNARE, que es troben a la membrana cel•lular i de la vesícula i que, a través de la unió paral•lela dels dominis catalítics, aproximen les membranes plasmàtica i vesicular possibilitant-ne la fusió
Malgrat posseir la maquinària necessària per a l’exocitosi, les neurones en desenvolupament no presenten estructures especialitzades per a la transmissió del senyal com són les sinapsis, i es creu que el paper de les proteïnes del complex SNARE rau en el manteniment de la homeòstasi de membrana. Conceptualment, és fàcil pensar que la guia axonal i la migració actuïn a través del control precís de la dinàmica de la membrana, augmentant localment la superfície de la neurona i expandint-la en la direcció del creixement.
En aquesta tesi hem investigat el paper de la dinàmica de membrana en la guia axonal i la migració. Concretament, ens hem centrat en l’estudi de la interacció del receptor de la Netrina-1 amb les proteïnes del complex SNARE en dos sistemes bàsics per a l’establiment de connexions del cervell: la guia dels axons de neurones de l’hipocamp i la migració de les neurones del llavi ròmbic atrets cap a una font de Netrina-1. També hem estudiat l’efecte del silenciament de les proteïnes del complex SNARE en dos paradigmes de guia axonal in vivo: la navegació dels axons de les cèl•lules comissurals de la medul•la espinal cap a, a través i més enllà de la línia mitja, i la innervació de l’extremitat inferior per part de les motoneurones d’embrions de pollastre. El tercer focus d’atenció ha estat l’estudi de la dinàmica de membrana i l’exocitosi al con de creixement de neurones d’hipocamp murí en resposta a estímuls quimioatraients de Netrina-1.
Els resultats obtinguts durant aquesta tesi han demostrat que el receptor de la atractiu de la Netrina-1 DCC interacciona in vivo amb les proteïnes del complex SNARE Sintaxina1 i TI-VAMP, però no amb SNAP25 o VAMP2 en cèl•lules d’hipocamp i neurones migrants del llavi ròmbic inferior. A més, la interacció de DCC amb Sintaxina1 està regulada pel lligand, però l’exocitosi del receptor de Netrina-1 no es veu afectada per tractaments amb toxines que proteolitzen Sintaxina1. Hem descrit que les proteïnes del complex SNARE són imprescindibles per a la guia dels axons de neurones comissurals i motoneurones , perquè el silenciament de Sintaxina1, SNAP25, VAMP2 o TI-VAMP causa defectes en la navegació dels seus axons compatibles amb alteracions de diversos sistemes (molècula guia-receptor) de guia axonal. Per últim, hem descrit la dinàmica de membrana i l’exocitosi a nivell del con de creixement amb una tècnica innovadora, que permet la monitorització de l’exocitosi en temps real, i, i hem descrit com la Netrina-1 incrementa l’exocitosi dependent de proteïnes SNARE a nivell del con de creixement i les vies de senyalització que hi estan implicades.Role of Synaptic Proteins and Exocytosis in Axon Guidance and Migration. Axon guidance and migration are two similar processes which are key to the development of the nervous system by allowing the correct localization and innervation of neurons. They regulate the elongation of the axon and the movement of cells by the use of guidance molecules which act as chemoattractants or chemorepellents at short and long ranges. A second crucial component in the nervous system functionality is exocytosis. It allows the communication of neighboring cells by the fusion of neurotransmitter-containing vesicles with the plasma membrane and the release of the vesicle contents to the extracellular space, a process mediated by the SNARE proteins. SNARE proteins located at the vesicle and the plasma membranes interact and bring the two membranes into close apposition, thereby facilitation fusion. Developing neurons have a vast array of synaptic proteins whose function is thought to reside in the regulation of membrane homeostasis. It is plausible to think that axon guidance and migration may act thru the precise control of membrane dynamics at discrete locations of the growth cone/leading edge, thereby expanding the neuron on the direction of growth. In this thesis we have analyzed the role of SNARE-mediated exocytosis in axon guidance and migration. We have focused our studies in the analysis of the interaction between the guidance receptor DCC and SNARE proteins in the attraction of hippocampal axons and migrating neurons of the lower rhombic lip towards a Netrin-1 source. We have also studied the role of SNARE proteins in two axon guidance paradigms such as the navigation of commissural axons of the spinal cord and motoneurons. Furthermore, we have also investigated Netrin-1-induced exocytosis in growth cones using live imaging techniques. Our results demonstrate the necessary participation of SNARE proteins and SNARE-mediated exocytosis in axon guidance and migration; reveal a ligand-regulated interaction between the Netrin-1 receptor DCC and the SNAREs Syntaxin1 and TI-VAMP; and show that Netrin-1 triggers SNARE-mediated exocytosis in the growth cone.