Journal articles: 'Clustered protocadherins'

1

Chen, W. V., and T. Maniatis. "Clustered protocadherins." Development 140, no. 16 (2013): 3297–302. http://dx.doi.org/10.1242/dev.090621.

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Ravi, Vydianathan, Wei-Ping Yu, Nisha E. Pillai, et al. "Cyclostomes Lack Clustered Protocadherins." Molecular Biology and Evolution 33, no. 2 (2015): 311–15. http://dx.doi.org/10.1093/molbev/msv252.

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Walujkar, Sanket P., Raul Araya-Sechhi, and Marcos Sotomayor. "Simulated Forced Unbinding of Clustered Protocadherins." Biophysical Journal 112, no. 3 (2017): 449a. http://dx.doi.org/10.1016/j.bpj.2016.11.2406.

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Nicoludis, John M., Anna G. Green, Sanket Walujkar, et al. "Interaction specificity of clustered protocadherins inferred from sequence covariation and structural analysis." Proceedings of the National Academy of Sciences 116, no. 36 (2019): 17825–30. http://dx.doi.org/10.1073/pnas.1821063116.

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Clustered protocadherins, a large family of paralogous proteins that play important roles in neuronal development, provide an important case study of interaction specificity in a large eukaryotic protein family. A mammalian genome has more than 50 clustered protocadherin isoforms, which have remarkable homophilic specificity for interactions between cellular surfaces. A large antiparallel dimer interface formed by the first 4 extracellular cadherin (EC) domains controls this interaction. To understand how specificity is achieved between the numerous paralogs, we used a combination of structural and computational approaches. Molecular dynamics simulations revealed that individual EC interactions are weak and undergo binding and unbinding events, but together they form a stable complex through polyvalency. Strongly evolutionarily coupled residue pairs interacted more frequently in our simulations, suggesting that sequence coevolution can inform the frequency of interaction and biochemical nature of a residue interaction. With these simulations and sequence coevolution, we generated a statistical model of interaction energy for the clustered protocadherin family that measures the contributions of all amino acid pairs at the interface. Our interaction energy model assesses specificity for all possible pairs of isoforms, recapitulating known pairings and predicting the effects of experimental changes in isoform specificity that are consistent with literature results. Our results show that sequence coevolution can be used to understand specificity determinants in a protein family and prioritize interface amino acid substitutions to reprogram specific protein–protein interactions.

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Jin, Yongfeng, and Hao Li. "Revisiting Dscam diversity: lessons from clustered protocadherins." Cellular and Molecular Life Sciences 76, no. 4 (2018): 667–80. http://dx.doi.org/10.1007/s00018-018-2951-4.

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Han, Meng-Hsuan, Chengyi Lin, Shuxia Meng, and Xiaozhong Wang. "Proteomics Analysis Reveals Overlapping Functions of Clustered Protocadherins." Molecular & Cellular Proteomics 9, no. 1 (2009): 71–83. http://dx.doi.org/10.1074/mcp.m900343-mcp200.

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Lefebvre, Julie L. "Neuronal territory formation by the atypical cadherins and clustered protocadherins." Seminars in Cell & Developmental Biology 69 (September 2017): 111–21. http://dx.doi.org/10.1016/j.semcdb.2017.07.040.

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Flaherty, Erin, and Tom Maniatis. "The role of clustered protocadherins in neurodevelopment and neuropsychiatric diseases." Current Opinion in Genetics & Development 65 (December 2020): 144–50. http://dx.doi.org/10.1016/j.gde.2020.05.041.

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Goodman, Kerry Marie, Rotem Rubinstein, Chan Aye Thu та ін. "Structural Basis of Diverse Homophilic Recognition by Clustered α- and β-Protocadherins". Neuron 90, № 4 (2016): 709–23. http://dx.doi.org/10.1016/j.neuron.2016.04.004.

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Biswas, S., M. R. Emond та J. D. Jontes. "The clustered protocadherins Pcdhα and Pcdhγ form a heteromeric complex in zebrafish". Neuroscience 219 (вересень 2012): 280–89. http://dx.doi.org/10.1016/j.neuroscience.2012.05.058.

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Kim, Hyunsoo, Noriko Takegahara, and Yongwon Choi. "Protocadherin-7 Regulates Monocyte Migration Through Regulation of Small GTPase RhoA and Rac1." International Journal of Molecular Sciences 26, no. 2 (2025): 572. https://doi.org/10.3390/ijms26020572.

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Protocadherin-7 (Pcdh7) is a member of the non-clustered protocadherin δ1 subgroup within the cadherin superfamily. Pcdh7 has been shown to control osteoclast differentiation via the protein phosphatase 2A (PP2A)–glycogen synthase kinase-3β (GSK3β)–small GTPase signaling axis. As protocadherins serve multiple biological functions, a deeper understanding of Pcdh7’s biological features is valuable. Using an in vitro mouse monocyte cell culture system, we demonstrate that Pcdh7 plays a role in regulating monocyte migration by modulating the small GTPases RhoA and Rac1. Pcdh7-deficient (Pcdh7−/−) bone marrow-derived monocytes exhibited impaired migration along with the reduced activation of RhoA and Rac1. This impaired migration was rescued by transduction with constitutively active forms of RhoA and Rac1. Treatment with the PP2A-specific activator DT-061 enhanced cell migration, whereas treatment with the GSK3β-specific inhibitor AR-A014418 inhibited migration in wild-type monocytes. In contrast, treatment with DT-061 failed to restore the impaired migration in Pcdh7−/− monocytes. These findings suggest the involvement of PP2A and GSK3β in monocyte migration, although the forced activation of PP2A alone is insufficient to restore impaired migration in Pcdh7−/− monocytes. Taken together, these results indicate that Pcdh7 regulates monocyte migration through the activation of RhoA and Rac1. Given the pivotal role of cell migration in both physiological and pathological processes, our findings provide a foundation for future research into therapeutic strategies targeting Pcdh7-regulated migration.

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Nicoludis, John M., Sze-Yi Lau, Charlotta P. I. Schärfe, Debora S. Marks, Wilhelm A. Weihofen, and Rachelle Gaudet. "Structure and Sequence Analyses of Clustered Protocadherins Reveal Antiparallel Interactions that Mediate Homophilic Specificity." Structure 23, no. 11 (2015): 2087–98. http://dx.doi.org/10.1016/j.str.2015.09.005.

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Harrison, Oliver J., Julia Brasch, Phinikoula S. Katsamba та ін. "Family-wide Structural and Biophysical Analysis of Binding Interactions among Non-clustered δ-Protocadherins". Cell Reports 30, № 8 (2020): 2655–71. http://dx.doi.org/10.1016/j.celrep.2020.02.003.

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Kim, S. Y., J. W. Mo, S. Han, et al. "The expression of non-clustered protocadherins in adult rat hippocampal formation and the connecting brain regions." Neuroscience 170, no. 1 (2010): 189–99. http://dx.doi.org/10.1016/j.neuroscience.2010.05.027.

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Goodman, Kerry M., Rotem Rubinstein, Hanbin Dan, et al. "Protocadherin cis-dimer architecture and recognition unit diversity." Proceedings of the National Academy of Sciences 114, no. 46 (2017): E9829—E9837. http://dx.doi.org/10.1073/pnas.1713449114.

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Clustered protocadherins (Pcdhs) mediate numerous neural patterning functions, including neuronal self-recognition and non–self-discrimination to direct self-avoidance among vertebrate neurons. Individual neurons stochastically express a subset of Pcdh isoforms, which assemble to form a stochastic repertoire of cis-dimers. We describe the structure of a PcdhγB7 cis-homodimer, which includes the membrane-proximal extracellular cadherin domains EC5 and EC6. The structure is asymmetric with one molecule contributing interface surface from both EC5 and EC6, and the other only from EC6. Structural and sequence analyses suggest that all Pcdh isoforms will dimerize through this interface. Site-directed mutants at this interface interfere with both Pcdh cis-dimerization and cell surface transport. The structure explains the known restrictions of cis-interactions of some Pcdh isoforms, including α-Pcdhs, which cannot form homodimers. The asymmetry of the interface approximately doubles the size of the recognition repertoire, and restrictions on cis-interactions among Pcdh isoforms define the limits of the Pcdh recognition unit repertoire.

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Lefebvre, Julie L. "ISDN2014_0427: Dendrite self‐avoidance and self/non‐self recognition in mammalian neurons is mediated by clustered protocadherins." International Journal of Developmental Neuroscience 47, Part_A (2015): 128–29. http://dx.doi.org/10.1016/j.ijdevneu.2015.04.342.

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Mountoufaris, George, Daniele Canzio, Chiamaka L. Nwakeze, Weisheng V. Chen, and Tom Maniatis. "Writing, Reading, and Translating the Clustered Protocadherin Cell Surface Recognition Code for Neural Circuit Assembly." Annual Review of Cell and Developmental Biology 34, no. 1 (2018): 471–93. http://dx.doi.org/10.1146/annurev-cellbio-100616-060701.

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The ability of neurites of individual neurons to distinguish between themselves and neurites from other neurons and to avoid self (self-avoidance) plays a key role in neural circuit assembly in both invertebrates and vertebrates. Similarly, when individual neurons of the same type project into receptive fields of the brain, they must avoid each other to maximize target coverage (tiling). Counterintuitively, these processes are driven by highly specific homophilic interactions between cell surface proteins that lead to neurite repulsion rather than adhesion. Among these proteins in vertebrates are the clustered protocadherins (Pcdhs), and key to their function is the generation of enormous cell surface structural diversity. Here we review recent advances in understanding how a Pcdh cell surface code is generated by stochastic promoter choice; how this code is amplified and read by homophilic interactions between Pcdh complexes at the surface of neurons; and, finally, how the Pcdh code is translated to cellular function, which mediates self-avoidance and tiling and thus plays a central role in the development of complex neural circuits. Not surprisingly, Pcdh mutations that diminish homophilic interactions lead to wiring defects and abnormal behavior in mice, and sequence variants in the Pcdh gene cluster are associated with autism spectrum disorders in family-based genetic studies in humans.

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Dilling, Christina, Norbert Roewer, Carola Y. Förster, and Malgorzata Burek. "Multiple protocadherins are expressed in brain microvascular endothelial cells and might play a role in tight junction protein regulation." Journal of Cerebral Blood Flow & Metabolism 37, no. 10 (2017): 3391–400. http://dx.doi.org/10.1177/0271678x16688706.

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Protocadherins (Pcdhs) are a large family of cadherin-related molecules. They play a role in cell adhesion, cellular interactions, and development of the central nervous system. However, their expression and role in endothelial cells has not yet been characterized. Here, we examined the expression of selected clustered Pcdhs in endothelial cells from several vascular beds. We analyzed human and mouse brain microvascular endothelial cell (BMEC) lines and primary cells, mouse myocardial microvascular endothelial cell line, and human umbilical vein endothelial cells. We examined the mRNA and protein expression of selected Pcdhs using RT-PCR, Western blot, and immunostaining. A strong mRNA expression of Pcdhs was observed in all endothelial cells tested. At the protein level, Pcdhs-gamma were detected using an antibody against the conserved C-terminal domain of Pcdhs-gamma or an antibody against PcdhgC3. Deletion of highly expressed PcdhgC3 led to differences in the tight junction protein expression and mRNA expression of Wnt/mTOR (mechanistic target of rapamycin) pathway genes as well as lower transendothelial electrical resistance. Staining of PcdhgC3 showed diffused cytoplasmic localization in mouse BMEC. Our results suggest that Pcdhs may play a critical role in the barrier-stabilizing pathways at the blood–brain barrier.

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Mancini, Maria, Silvia Bassani, and Maria Passafaro. "Right Place at the Right Time: How Changes in Protocadherins Affect Synaptic Connections Contributing to the Etiology of Neurodevelopmental Disorders." Cells 9, no. 12 (2020): 2711. http://dx.doi.org/10.3390/cells9122711.

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During brain development, neurons need to form the correct connections with one another in order to give rise to a functional neuronal circuitry. Mistakes during this process, leading to the formation of improper neuronal connectivity, can result in a number of brain abnormalities and impairments collectively referred to as neurodevelopmental disorders. Cell adhesion molecules (CAMs), present on the cell surface, take part in the neurodevelopmental process regulating migration and recognition of specific cells to form functional neuronal assemblies. Among CAMs, the members of the protocadherin (PCDH) group stand out because they are involved in cell adhesion, neurite initiation and outgrowth, axon pathfinding and fasciculation, and synapse formation and stabilization. Given the critical role of these macromolecules in the major neurodevelopmental processes, it is not surprising that clinical and basic research in the past two decades has identified several PCDH genes as responsible for a large fraction of neurodevelopmental disorders. In the present article, we review these findings with a focus on the non-clustered PCDH sub-group, discussing the proteins implicated in the main neurodevelopmental disorders.

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Gray, Michelle E., and Marcos Sotomayor. "Crystal structure of the nonclassical cadherin-17 N-terminus and implications for its adhesive binding mechanism." Acta Crystallographica Section F Structural Biology Communications 77, no. 3 (2021): 85–94. http://dx.doi.org/10.1107/s2053230x21002247.

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The cadherin superfamily of calcium-dependent cell-adhesion proteins has over 100 members in the human genome. All members of the superfamily feature at least a pair of extracellular cadherin (EC) repeats with calcium-binding sites in the EC linker region. The EC repeats across family members form distinct complexes that mediate cellular adhesion. For instance, classical cadherins (five EC repeats) strand-swap their N-termini and exchange tryptophan residues in EC1, while the clustered protocadherins (six EC repeats) use an extended antiparallel `forearm handshake' involving repeats EC1–EC4. The 7D-cadherins, cadherin-16 (CDH16) and cadherin-17 (CDH17), are the most similar to classical cadherins and have seven EC repeats, two of which are likely to have arisen from gene duplication of EC1–2 from a classical ancestor. However, CDH16 and CDH17 lack the EC1 tryptophan residue used by classical cadherins to mediate adhesion. The structure of human CDH17 EC1–2 presented here reveals features that are not seen in classical cadherins and that are incompatible with the EC1 strand-swap mechanism for adhesion. Analyses of crystal contacts, predicted glycosylation and disease-related mutations are presented along with sequence alignments suggesting that the novel features in the CDH17 EC1–2 structure are well conserved. These results hint at distinct adhesive properties for 7D-cadherins.

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O'Leary, Robert, James E. Reilly, Hugo H. Hanson, Semie Kang, Nicole Lou та Greg R. Phillips. "A variable cytoplasmic domain segment is necessary for γ-protocadherin trafficking and tubulation in the endosome/lysosome pathway". Molecular Biology of the Cell 22, № 22 (2011): 4362–72. http://dx.doi.org/10.1091/mbc.e11-04-0283.

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Clustered protocadherins (Pcdhs) are arranged in gene clusters (α, β, and γ) with variable and constant exons. Variable exons encode cadherin and transmembrane domains and ∼90 cytoplasmic residues. The 14 Pcdh-αs and 22 Pcdh-γs are spliced to constant exons, which, for Pcdh-γs, encode ∼120 residues of an identical cytoplasmic moiety. Pcdh-γs participate in cell–cell interactions but are prominently intracellular in vivo, and mice with disrupted Pcdh-γ genes exhibit increased neuronal cell death, suggesting nonconventional roles. Most attention in terms of Pcdh-γ intracellular interactions has focused on the constant domain. We show that the variable cytoplasmic domain (VCD) is required for trafficking and organelle tubulation in the endolysosome system. Deletion of the constant cytoplasmic domain preserved the late endosomal/lysosomal trafficking and organelle tubulation observed for the intact molecule, whereas deletion or excision of the VCD or replacement of the Pcdh-γA3 cytoplasmic domain with that from Pcdh-α1 or N-cadherin dramatically altered trafficking. Truncations or internal deletions within the VCD defined a 26–amino acid segment required for trafficking and tubulation in the endolysosomal pathway. This active VCD segment contains residues that are conserved in Pcdh-γA and Pcdh-γB subfamilies. Thus the VCDs of Pcdh-γs mediate interactions critical for Pcdh-γ trafficking.

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Kim, Soo-Young, Shin Yasuda, Hidekazu Tanaka, Kanato Yamagata, and Hyun Kim. "Non-clustered protocadherin." Cell Adhesion & Migration 5, no. 2 (2011): 97–105. http://dx.doi.org/10.4161/cam.5.2.14374.

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Yagi, Takeshi. "Clustered protocadherin family." Development, Growth & Differentiation 50 (April 22, 2008): S131—S140. http://dx.doi.org/10.1111/j.1440-169x.2008.00991.x.

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Phillips, Greg R., Nicole LaMassa, and Yan Mei Nie. "Clustered protocadherin trafficking." Seminars in Cell & Developmental Biology 69 (September 2017): 131–39. http://dx.doi.org/10.1016/j.semcdb.2017.05.001.

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Brasch, Julia, Kerry M. Goodman, Alex J. Noble, et al. "Visualization of clustered protocadherin neuronal self-recognition complexes." Nature 569, no. 7755 (2019): 280–83. http://dx.doi.org/10.1038/s41586-019-1089-3.

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Hirayama, Teruyoshi, and Takeshi Yagi. "Regulation of clustered protocadherin genes in individual neurons." Seminars in Cell & Developmental Biology 69 (September 2017): 122–30. http://dx.doi.org/10.1016/j.semcdb.2017.05.026.

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Rubinstein, Rotem, Kerry Marie Goodman, Tom Maniatis, Lawrence Shapiro, and Barry Honig. "Structural origins of clustered protocadherin-mediated neuronal barcoding." Seminars in Cell & Developmental Biology 69 (September 2017): 140–50. http://dx.doi.org/10.1016/j.semcdb.2017.07.023.

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Kaneko, Ryosuke, Manabu Abe, Takahiro Hirabayashi та ін. "Roles of clustered genomic organization of Protocadherin-α on individual neuron specific Protocadherin-α choice". Neuroscience Research 65 (січень 2009): S89. http://dx.doi.org/10.1016/j.neures.2009.09.365.

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Tang, Yuanxiao, Zhilian Jia, Honglin Xu, Lin-tai Da та Qiang Wu. "Mechanism of REST/NRSF regulation of clustered protocadherin α genes". Nucleic Acids Research 49, № 8 (2021): 4506–21. http://dx.doi.org/10.1093/nar/gkab248.

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Abstract Repressor element-1 silencing transcription factor (REST) or neuron-restrictive silencer factor (NRSF) is a zinc-finger (ZF) containing transcriptional repressor that recognizes thousands of neuron-restrictive silencer elements (NRSEs) in mammalian genomes. How REST/NRSF regulates gene expression remains incompletely understood. Here, we investigate the binding pattern and regulation mechanism of REST/NRSF in the clustered protocadherin (PCDH) genes. We find that REST/NRSF directionally forms base-specific interactions with NRSEs via tandem ZFs in an anti-parallel manner but with striking conformational changes. In addition, REST/NRSF recruitment to the HS5–1 enhancer leads to the decrease of long-range enhancer-promoter interactions and downregulation of the clustered PCDHα genes. Thus, REST/NRSF represses PCDHα gene expression through directional binding to a repertoire of NRSEs within the distal enhancer and variable target genes.

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Goodman, Kerry M., Rotem Rubinstein, Julia Brasch, et al. "Clustered protocadherin molecular assembly and implications for neuronal self-avoidance." Acta Crystallographica Section A Foundations and Advances 73, a1 (2017): a50. http://dx.doi.org/10.1107/s0108767317099500.

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Okayama, Atsushi, Ryosuke Kaneko, and Takesi Yagi. "Analysis of clustered Protocadherin families using their gene-conversion mice." Neuroscience Research 65 (January 2009): S151. http://dx.doi.org/10.1016/j.neures.2009.09.763.

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Goodman, Kerry Marie, Rotem Rubinstein, Julia Brasch, et al. "Clustered protocadherin molecular assembly and implications for neuronal self-avoidance." Acta Crystallographica Section A Foundations and Advances 73, a2 (2017): C385. http://dx.doi.org/10.1107/s2053273317091884.

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Wu, Qiang. "Comparative Genomics and Diversifying Selection of the Clustered Vertebrate Protocadherin Genes." Genetics 169, no. 4 (2005): 2179–88. http://dx.doi.org/10.1534/genetics.104.037606.

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Golan-Mashiach, Michal, Moshe Grunspan, Rafi Emmanuel, Liron Gibbs-Bar, Rivka Dikstein, and Ehud Shapiro. "Identification of CTCF as a master regulator of the clustered protocadherin genes." Nucleic Acids Research 40, no. 8 (2011): 3378–91. http://dx.doi.org/10.1093/nar/gkr1260.

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Zou, C., W. Huang, G. Ying, and Qiang Wu. "Sequence analysis and expression mapping of the rat clustered protocadherin gene repertoires." Neuroscience 144, no. 2 (2007): 579–603. http://dx.doi.org/10.1016/j.neuroscience.2006.10.011.

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Kobayashi, Hiroaki, Kenji Takemoto, Makoto Sanbo, et al. "Isoform requirement of clustered protocadherin for preventing neuronal apoptosis and neonatal lethality." iScience 27, no. 4 (2024): 109606. http://dx.doi.org/10.1016/j.isci.2024.109606.

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May, Elizabeth, and Rachelle Gaudet. "BPS2025 - Surface delivery quantification reveals distinct trafficking efficiencies among clustered protocadherin isoforms." Biophysical Journal 124, no. 3 (2025): 228a. https://doi.org/10.1016/j.bpj.2024.11.1251.

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Modak, Debadrita. "Resolving the Mechanism of Adhesion Mediated by a Non-Clustered Delta-1 Protocadherin." Biophysical Journal 114, no. 3 (2018): 406a. http://dx.doi.org/10.1016/j.bpj.2017.11.2249.

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Etlioglu, Hakki E., Wei Sun, Zengjin Huang, Wei Chen, and Dietmar Schmucker. "Characterization of a Single Genomic Locus Encoding the Clustered Protocadherin Receptor Diversity inXenopus tropicalis." G3: Genes|Genomes|Genetics 6, no. 8 (2016): 2309–18. http://dx.doi.org/10.1534/g3.116.027995.

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Toyoda, Shunsuke, Masahumi Kawaguchi, Toshihiro Kobayashi, et al. "Developmental Epigenetic Modification Regulates Stochastic Expression of Clustered Protocadherin Genes, Generating Single Neuron Diversity." Neuron 82, no. 1 (2014): 94–108. http://dx.doi.org/10.1016/j.neuron.2014.02.005.

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Kim, S. Y., H. Sun Chung, W. Sun, and H. Kim. "Spatiotemporal expression pattern of non-clustered protocadherin family members in the developing rat brain." Neuroscience 147, no. 4 (2007): 996–1021. http://dx.doi.org/10.1016/j.neuroscience.2007.03.052.

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Meguro, Reiko, Ryuichi Hishida, Hiroaki Tsukano та ін. "Impaired clustered protocadherin-α leads to aggregated retinogeniculate terminals and impaired visual acuity in mice". Journal of Neurochemistry 133, № 1 (2015): 66–72. http://dx.doi.org/10.1111/jnc.13053.

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Kim, Hyunsoo, Noriko Takegahara, and Yongwon Choi. "Protocadherin-7 Regulates Osteoclast Differentiation through Intracellular SET-Binding Domain-Mediated RhoA and Rac1 Activation." International Journal of Molecular Sciences 22, no. 23 (2021): 13117. http://dx.doi.org/10.3390/ijms222313117.

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Protocadherin-7 (Pcdh7) is a member of the non-clustered protocadherin δ1 subgroup of the cadherin superfamily. Although the cell-intrinsic role of Pcdh7 in osteoclast differentiation has been demonstrated, the molecular mechanisms of Pcdh7 regulating osteoclast differentiation remain to be determined. Here, we demonstrate that Pcdh7 contributes to osteoclast differentiation by regulating small GTPases, RhoA and Rac1, through its SET oncoprotein binding domain. Pcdh7 is associated with SET along with RhoA and Rac1 during osteoclast differentiation. Pcdh7-deficient (Pcdh7−/−) cells showed abolished RANKL-induced RhoA and Rac1 activation, and impaired osteoclast differentiation. Impaired osteoclast differentiation in Pcdh7−/− cells was restored by retroviral transduction of full-length Pcdh7 but not by a Pcdh7 mutant that lacks SET binding domain. The direct crosslink of the Pcdh7 intracellular region induced the activation of RhoA and Rac1, which was not observed when Pcdh7 lacks the SET binding domain. Additionally, retroviral transduction of the constitutively active form of RhoA and Rac1 completely restored the impaired osteoclast differentiation in Pcdh7−/− cells. Collectively, these results demonstrate that Pcdh7 controls osteoclast differentiation by regulating RhoA and Rac1 activation through the SET binding domain.

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Kawamura, Nanami, Tomoki Osuka, Ryosuke Kaneko та ін. "Reciprocal Connections between Parvalbumin-Expressing Cells and Adjacent Pyramidal Cells Are Regulated by Clustered Protocadherin γ". eneuro 10, № 10 (2023): ENEURO.0250–23.2023. http://dx.doi.org/10.1523/eneuro.0250-23.2023.

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AbstractFunctional neural circuits in the cerebral cortex are established through specific neural connections between excitatory and various inhibitory cell types. However, the molecular mechanisms underlying synaptic partner recognition remain unclear. In this study, we examined the impact of clustered protocadherin-γ (cPcdhγ) gene deletion in parvalbumin-positive (PV+) cells on intralaminar and translaminar neural circuits formed between PV+and pyramidal (Pyr) cells in the primary visual cortex (V1) of male and female mice. First, we used whole-cell recordings and laser-scan photostimulation with caged glutamate to map excitatory inputs from layer 2/3 to layer 6. We found thatcPcdhγ-deficient PV+cells in layer 2/3 received normal translaminar inputs from Pyr cells through layers 2/3–6. Second, to further elucidate the effect on PV+-Pyr microcircuits within intralaminar layer 2/3, we conducted multiple whole-cell recordings. While the overall connection probability of PV+-Pyr cells remained largely unchanged, the connectivity of PV+-Pyr was significantly different between control and PV+-specificcPcdhγ-conditional knock-out (PV-cKO) mice. In control mice, the number of reciprocally connected PV+cells was significantly higher than PV+cells connected one way to Pyr cells, a difference that was not significant inPV-cKOmice. Interestingly, the proportion of highly reciprocally connected PV+cells to Pyr cells with large unitary IPSC (uIPSC) amplitudes was reduced inPV-cKOmice. Conversely, the proportion of middle reciprocally connected PV+cells to Pyr cells with large uIPSC amplitudes increased compared with control mice. This study demonstrated thatcPcdhγin PV+cells modulates their reciprocity with Pyr cells in the cortex.

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Kim, Hyunsoo, Noriko Takegahara та Yongwon Choi. "PP2A-Mediated GSK3β Dephosphorylation Is Required for Protocadherin-7-Dependent Regulation of Small GTPase RhoA in Osteoclasts". Cells 12, № 15 (2023): 1967. http://dx.doi.org/10.3390/cells12151967.

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Protocadherin-7 (Pcdh7) is a member of the non-clustered protocadherin δ1 subgroup of the cadherin superfamily. Pcdh7 has been revealed to control osteoclast differentiation by regulating Rho-family small GTPases, RhoA and Rac1, through its intracellular SET binding domain. However, the mechanisms by which small GTPases are regulated downstream of Pcdh7 remain unclear. Here, we demonstrate that protein phosphatase 2A (PP2A)-mediated dephosphorylation of Glycogen synthase kinase-3β (GSK3β) is required for Pcdh7-dependent activation of RhoA during osteoclast differentiation. Pcdh7-deficient (Pcdh7−/−) cells showed impaired PP2A activity, despite their normal expression of PP2A. GSK3β, whose activity is regulated by its inhibitory phosphorylation at Ser9, was dephosphorylated during osteoclast differentiation in a Pcdh7-dependent manner. Inhibition of protein phosphatase by okadaic acid reduced dephosphorylation of GSK3β in Pcdh7+/+ cells, while activation of PP2A by DT−061 rescued impaired dephosphorylation of GSK3β in Pcdh7−/− cells. Inhibition of GSK3β by AR−A014418 inhibited RANKL-induced RhoA activation and osteoclast differentiation in Pcdh7+/+ cells. On the other hand, DT-061 treatment rescued impaired RhoA activation and RANKL-induced osteoclast differentiation in Pcdh7−/− cells. Taken together, these results demonstrate that PP2A dephosphorylates GSK3β and thereby activates it in a Pcdh7-dependent manner, which is required for activation of small GTPase RhoA and proper osteoclast differentiation.

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Xu, Lichao, Yue Zheng, Xuejing Li, et al. "Abnormal neocortex arealization and Sotos-like syndrome–associated behavior in Setd2 mutant mice." Science Advances 7, no. 1 (2021): eaba1180. http://dx.doi.org/10.1126/sciadv.aba1180.

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Proper formation of area identities of the cerebral cortex is crucial for cognitive functions and social behaviors of the brain. It remains largely unknown whether epigenetic mechanisms, including histone methylation, regulate cortical arealization. Here, we removed SETD2, the methyltransferase for histone 3 lysine-36 trimethylation (H3K36me3), in the developing dorsal forebrain in mice and showed that Setd2 is required for proper cortical arealization and the formation of cortico-thalamo-cortical circuits. Moreover, Setd2 conditional knockout mice exhibit defects in social interaction, motor learning, and spatial memory, reminiscent of patients with the Sotos-like syndrome bearing SETD2 mutations. SETD2 maintains the expression of clustered protocadherin (cPcdh) genes in an H3K36me3 methyltransferase–dependent manner. Aberrant cortical arealization was recapitulated in cPcdh heterozygous mice. Together, our study emphasizes epigenetic mechanisms underlying cortical arealization and pathogenesis of the Sotos-like syndrome.

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Chen, Kelan, Jiang Hu, Darcy L. Moore, et al. "Genome-wide binding and mechanistic analyses of Smchd1-mediated epigenetic regulation." Proceedings of the National Academy of Sciences 112, no. 27 (2015): E3535—E3544. http://dx.doi.org/10.1073/pnas.1504232112.

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Structural maintenance of chromosomes flexible hinge domain containing 1 (Smchd1) is an epigenetic repressor with described roles in X inactivation and genomic imprinting, but Smchd1 is also critically involved in the pathogenesis of facioscapulohumeral dystrophy. The underlying molecular mechanism by which Smchd1 functions in these instances remains unknown. Our genome-wide transcriptional and epigenetic analyses show that Smchd1 binds cis-regulatory elements, many of which coincide with CCCTC-binding factor (Ctcf) binding sites, for example, the clustered protocadherin (Pcdh) genes, where we show Smchd1 and Ctcf act in opposing ways. We provide biochemical and biophysical evidence that Smchd1–chromatin interactions are established through the homodimeric hinge domain of Smchd1 and, intriguingly, that the hinge domain also has the capacity to bind DNA and RNA. Our results suggest Smchd1 imparts epigenetic regulation via physical association with chromatin, which may antagonize Ctcf-facilitated chromatin interactions, resulting in coordinated transcriptional control.

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Kanadome, Takashi, Natsumi Hoshino, Takeharu Nagai, Takeshi Yagi, and Tomoki Matsuda. "Protocol to visualize trans-interaction of clustered protocadherin using cIPAD, a fluorescent indicator, in cultured human cells and mouse neurons." STAR Protocols 5, no. 1 (2024): 102844. http://dx.doi.org/10.1016/j.xpro.2024.102844.

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McDermott, Nicole L., Amel Saadi, Mario Cocco, et al. "Epigenetic control of the protocadherin-gamma locus provides a potential source of cell surface codes in B cell differentiation." Journal of Immunology 204, no. 1_Supplement (2020): 153.17. http://dx.doi.org/10.4049/jimmunol.204.supp.153.17.

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Abstract Cellular adhesion plays an important role in determining homing and retention of cells to specific locations. Antibody-secreting plasma cells (PCs) depend on access to niche microenvironments for survival, but the factors that control the adhesion behaviour of different PCs are incompletely understood. We noted that cadherin superfamily protocadherin (PCDH) genes showed a dynamic pattern of regulation during differentiation of human PCs. Clustered PCDHs are split into 3 gene loci (α, β and γ). Choice of variable first exons, which encode the extracellular domain is determined by selective promoter usage. This is controlled by CTCF and enhancer looping. In neurons, PCDH expression generates single cell identity codes important for synapse formation. Tracking differentiation from B cell to PC stage, ATAC-seq demonstrated selective accessibility over the PCDHG but not PCDHA or PCDHB loci. ChIP-seq for CTCF, H3K4me3 and H3K27ac revealed active promoter marks and CTCF interactions within the PCDHG locus. Flow cytometry confirmed heterogenous expression of PCDHG family members during PC differentiation in line with mRNA patterns. Consistent with post-translational regulation, PCDHG surface expression was additionally increased by ADAM protease inhibition. We conclude that the B cell lineage shows selective epigenetic accessibility at the PCDHG locus and expression of PCDHG family members upon differentiation to the PC state. This is coupled with patterns of CTCF occupancy implicated in regulating surface identity codes. We conclude that epigenetic control of the PCDHG locus provides a potential source of cell surface codes amongst differentiating PCs.

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Modak, Debadrita, та Marcos Sotomayor. "Identification of an adhesive interface for the non-clustered δ1 protocadherin-1 involved in respiratory diseases". Communications Biology 2, № 1 (2019). http://dx.doi.org/10.1038/s42003-019-0586-0.

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Abstract Cadherins form a large family of calcium-dependent adhesive proteins involved in morphogenesis, cell differentiation, and neuronal connectivity. Non-clustered δ1 protocadherins form a cadherin subgroup of proteins with seven extracellular cadherin (EC) repeats and cytoplasmic domains distinct from those of classical cadherins. Non-clustered δ1 protocadherins mediate homophilic adhesion and have been implicated in various diseases including asthma, autism, and cancer. Here we present X-ray crystal structures of human Protocadherin-1 (PCDH1), a δ1-protocadherin member essential for New World Hantavirus infection that is typically expressed in the brain, airway epithelium, skin keratinocytes, and lungs. The structures suggest a binding mode that involves antiparallel overlap of repeats EC1 to EC4. Mutagenesis combined with binding assays and biochemical experiments validated this mode of adhesion. Overall, these results reveal the molecular mechanism underlying adhesiveness of PCDH1 and δ1-protocadherins, also shedding light on PCDH1’s role in maintaining airway epithelial integrity, the loss of which causes respiratory diseases.

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Journal articles on the topic 'Clustered protocadherins'

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