Dissertations / Theses on the topic 'Pituitary gland function'

The differentiation of growth hormone producing somatotropes in the pituitary gland is dependent upon signaling and transcription factors produced both within and outside the gland. In order to better understand this fundamental process, we have focused on investigating the contribution of forkhead factors FOXO1 and FOXO3. We sought to elucidate whether FOXO1 is sufficient to drive somatotrope differentiation in an over-expression mouse model, identify potential functional redundancy between closely related forkhead family members, and to specify the genetic targets of FOXO1 binding in the pituitary gland. Using a combination of mouse models and molecular techniques we have established a role for Foxo1 in early embryonic development, generated a somatotrope-specific FOXO1 binding enrichment library, revealed functional redundancy between FOXO1 and FOXO3 in the pituitary gland, and discovered a novel protein-protein interaction with YBX1. These results demonstrate FOXO factors are important for pituitary gland formation and function during both pre- and postnatal periods.

Various mouse models have allowed for identification of several transcription factors that are necessary for pituitary development. Lesions in the transcription factor genes result in pituitary hormone deficiency. Hormone deficiencies occur in approximately one in 4000 live births. Pituitary hormone deficiency may occur due to loss of a single hormone causing isolated hormone deficiency or several hormones leading to combined pituitary hormone deficiency (CPHD). Defects in genes such as LHX3, LHX4, RPX, PROP1, and PIT1 are known to contribute to CPHD in humans. FOXO1 is a member of a large family of forkhead transcription factors. FOXO1 is expressed in various tissues where it functions to regulate metabolism, maintenance of cell differentiation, vascular development, cell cycle progression and apoptosis. Previous studies in our laboratory found that FOXO1 is expressed in different subsets of pituitary cells during embryonic pituitary development, with almost 50% of GH positive somatotropes also immunopositive for FOXO1. However, the roles of FOXO1 during pituitary development have not been extensively explored. Therefore, this research focuses on the contributions of FOXO1 to pituitary development and exploration of FOXO1 as a candidate gene for CPHD. In this study, a mouse model (Foxo1 cKO) is used wherein the Foxo1 gene has been deleted in the pituitary gland by Cre-LoxP recombination system. First, expression of several genes was examined that might be associated with loss of FOXO1 in the pituitary with an aim to place FOXO1 within the hierarchy of transcription factors critical for pituitary development. The early pituitary organizers, PITX2, PITX3, LHX3, LHX4, are not affected due to deletion of Foxo1 suggesting that FOXO1 is not critical for the initial induction of oral ectoderm to form Rathke’s pouch during the early stages of pituitary development. PIT1 marks the progenitors committed to becoming somatotropes, thyrotropes or lactotropes. No apparent difference in Pit1 mRNA level as well as PIT1 immunostaining between cKO and wildtype embryos suggests that FOXO1 does not affect the commitment of progenitors to cells of the PIT1 lineage. The most significant effects of Foxo1 deletion in the pituitary gland was observed in somatotrope differentiation. There was a drastically decreased mRNA level of Ghrhr, a marker of terminally differentiated somatotropes as well as reduced expression of Neurod4 in Foxo1 cKO embryos compared to wildtype littermates. NEUROD4 is downstream of FOXO1. Another study suggests that Neurod4 deletion in the pituitary gland affects maturation of somatotrope while preserving other cell types of anterior pituitary. NEUROD4 is essential for expression of Ghrhr during embryonic development as Neurod4 deletion results in fewer somatotropes and a complete lack of Ghrhr. Therefore, it can be implied that NEUROD4 may act as an intermediate in FOXO1 mediated terminal somatotrope differentiation and loss of FOXO1 in pituitary tissue is impeding somatotrope differentiation. We also assessed the functional consequences of loss of FOXO1 in postnatal mice. The delay in differentiation of somatotropes that was evident during embryonic development seems to have recovered by P10. Therefore, we suggest that FOXO1 is important for somatotrope differentiation embryonically. FOXO1 is important for somatotrope function postnatally also. Gh1 expression, GH pituitary content and serum IGF1 levels are significantly reduced at P21. However, the cKO mice do not exhibit any growth deficit indicating that FOXO1 is dispensable for postnatal somatotrope expansion and growth. Our results show that the embryonic somatotrope phenotype associated with deletion of Foxo1 does not result in any morphological changes in postnatal cKO mice. A gene expression profiling study was done to ascertain the changes in transcriptome of the embryonic pituitary lacking FOXO1. We identified Slc25a33 and Deptor as differentially expressed genes. SLC25A33 is involved with transport of pyrimidine nucleotides across mitochondrial membrane and such transport is essential for mitochondrial DNA and RNA metabolism. Studies involving overexpression of Slc25a33 in human cells have shown it enhances cell size and mitochondrial thymidine triphosphate level but decreases ROS. Its knockdown causes depletion of mitochondrial DNA, reduced oxidative phosphorylation, cell size, and mitochondrial UTP levels, and increased ROS levels. SLC25A33 essentially maintains mitochondrial function as it regulates mitochondrial DNA replication and the ratio of transcription of mitochondrial genes relative to nuclear genes. DEPTOR acts as an intermediate in BAF60c-induced AKT activation that results in a metabolic switch from oxidative phosphorylation to glycolysis in fast-twitch myofiber. Such a switch is considered to protect mice from diet induced insulin resistance and glucose intolerance in diabetic state. In differentiating cells, significant oxidative damage occurs, which can be attributed to higher mitochondrial activity. Embryonic stem cells undergoing differentiation exhibit increased mitochondrial activity associated with mitochondrial DNA replication to encode mitochondrial electron transport chain components. During osteogenic differentiation, there is a significant increase in expression of Slc25a33, with concomitant increase in mitochondrial oxygen consumption. Similar changes have been reported during spontaneous embryonic stem cell differentiation with increase in ROS production associated with differentiation. Identification of Slc25a33 and Deptor brings to our attention, a possible mechanism which might explain the delayed somatotrope differentiation phenotype in Foxo1 cKO pituitary. We hypothesize that loss of FOXO1 and resulting suppression of Slc25a33 and Deptor results in perturbation in mitochondrial replication and imbalances ROS homeostasis, which thereby affects mitochondrial function. This hinders the somatotrope’s ability to switch to more energetically demanding metabolic pathways that are essential during terminal differentiation. A metabolic switch may be the key to the terminal differentiation of mature somatotropes from their committed progenitor cells. Our findings thus provide new insights and opens avenues for future research to investigate mechanisms of somatotrope development.

Spring-born ram lambs were used to examine: (1) sexual maturational changes in LH, FSH and prolactin (PRL) secretion, testicular gonadotropin receptors, and testicular size and function; (2) predictability of yearling ram reproductive function from juvenile testicular size and reproductive hormone measurements. Despite continuous increases in testis size, serum LH-profile characteristics became greatest between 2 and 4 months and declined thereafter. However, LH-peak frequency increased by about 2-fold between 6 and 7 months; this was associated with marked increases in testosterone (T) secretion and spermatogenic function. Mean FSH and PRL levels were maximum at 2 months and 3 to 5 months, respectively, and decreased thereafter. Increases in steroidogenic and spermatogenic function were due partly to increases in testicular content of LH and FSH receptors. Yearling ram testis size and spermatogenic function were predictable from testis size at 5 to 6 months, neonatal (50 days) secretion of LH and T, and pubertal (150 days) secretion of T. However, combinations of testicular size and reproductive hormone measurements provided greater predictive power.

碩士
元培科學技術學院
影像醫學研究所
95
Recently, children with development disease were discovered in a lot of pediatric departments. General clinical diagnosis of this kind disease included height, weight, blood, urine and bone age measurements. Special examinations included chromosome examination, radioimmunoassay, computed tomography and magnetic resonance imaging. When growth hormone was insufficient, the last two methods could be used for the differentiation of brain structure abnormality and brain tumor. Generally, pituitary gland was evaluated by the changes of shape, size and height in different sections of image. However, computed tomography usually has scruple with the radiation dose, especially for children. In addition, two-dimensional images always could not provide effective information sufficiently. Therefore, the non-invasive magnetic resonance imaging method was employed to measure the pituitary volumes of children in Taiwan area. From our study, the comparison exterior between normal with exceptional pituitary gland in Taiwan area could be built. Furthermore, the information could also be provided as the reference of clinical diagnosis in pediatrics department. Children under the age of 14 and undergoing brain MRI for endocrines development disease or for other diagnostic purpose were our major subjects. Sixty-three children were eligible (mean age, 5.8 years). Forty images were collected by modern MRI Spoiled Gradient-recalled Acquisition in the Steady-state (SPGR) technique for each subject. Direct pituitary volumes were then measured after multi-plane reconstruction (MPR) for each image. In total, forty images of axial and forty images of saggittal plane were reconstructed separately for each subject. Due to the irregular three dimensional shape of pituitary gland, its volume measurement is a big challenge. In order to improve the accuracy and avoid errors, the area of each image was measured six times and then the average value was calculated. Finally, the volume of each plane was obtained by summarizing all averaged images of that plane. To confirm the trusty of our results, the volumes and errors of a 500 mm3 and a 250 mm3 image test phantoms were measured for calibration. The volume of pituitary gland for each subject could then be corrected by statistical method. Our results indicated that the average volumes of sexual precocity children were higher than normal children (p < 0.05), which had statistically significance. The average volumes of development delay children were smaller than normal children (p > 0.05), however did not have statistically significance. We thought the reason could be as following: the disease of development delay always found in much younger children, who usually have smaller volume of pituitary gland, and therefore generated more deviations from the averaged data of normal subjects.

Project aims to determine "mechanisms of anterior pituitary gland function and testicular steroidogenesis which result in the increased testosterone secretion observed in male bovine treated with the GnRh agonist deslorelin".