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Peter G Stanton - One of the best experts on this subject based on the ideXlab platform.
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Claudin-11 and occludin are major contributors to Sertoli Cell tight junction function, in vitro
Asian Journal of Andrology, 2016Co-Authors: Mark J. Mccabe, Caroline F.h. Foo, Marcel E. Dinger, Peter M. Smooker, Peter G StantonAbstract:The Sertoli Cell tight junction (TJ) is the key component of the blood-testis barrier, where it sequesters developing germ Cells undergoing spermatogenesis within the seminiferous tubules. Hormonally regulated claudin-11 is a critical transmembrane protein involved in barrier function and its murine knockout results in infertility. We aimed to assess quantitatively the significance of the contribution of claudin-11 to TJ function, in vitro, using siRNA-mediated gene silencing. We also conducted an analysis of the contribution of occludin, another intrinsic transmembrane protein of the TJ. Silencing of claudin-11 and/or occludin was conducted using siRNA in an immature rat Sertoli Cell culture model. Transepithelial electrical resistance was used to assess quantitatively TJ function throughout the culture. Two days after siRNA treatment, Cells were fixed for immunocytochemical localization of junction proteins or lyzed for RT-PCR assessment of mRNA expression. Silencing of claudin-11, occludin, or both resulted in significant decreases in TJ function of 55% (P < 0.01), 51% (P < 0.01), and 62% (P < 0.01), respectively. Data were concomitant with significant decreases in mRNA expression and marked reductions in the localization of targeted proteins to the Sertoli Cell TJ. We provide quantitative evidence that claudin-11 contributes significantly (P < 0.01) to Sertoli Cell TJ function in vitro. Interestingly, occludin, which is hormonally regulated but not implicated in infertility until late adulthood, is also a significant (P < 0.01) contributor to barrier function. Our data are consistent with in vivo studies that clearly demonstrate a role for these proteins in maintaining normal TJ barrier structure and function.
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androgen initiates Sertoli Cell tight junction formation in the hypogonadal hpg mouse
Biology of Reproduction, 2012Co-Authors: Peter K. Nicholls, Peter G Stanton, Mark J. Mccabe, Charles M Allan, Kirsten J MctavishAbstract:Sertoli Cell tight junctions (TJs) form at puberty as a major component of the blood-testis barrier (BTB), which is essential for spermatogenesis. This study characterized the hormonal induction of functional Sertoli Cell TJ formation in vivo using the gonadotropin-deficient hypogonadal (hpg) mouse that displays prepubertal spermatogenic arrest. Androgen actions were determined in hpg mice treated for 2 or 10 days with dihydrotestosterone (DHT). Follicle-stimulating hormone (FSH) actions were studied in hpg mice expressing transgenic human FSH (hpg+tgFSH) with or without DHT treatment. TJ formation was examined by mRNA expression and immunolocalization of TJ proteins claudin-3 and claudin-11, and barrier functionality was examined by biotin tracer permeability. Immunolocalization of claudin-3 and claudin-11 was extensive at wild-type (wt) Sertoli Cell TJs, which functionally excluded permeability tracer. In contrast, seminiferous tubules of hpg testes lacked claudin-3, but claudin-11 protein was present in adluminal regions of Sertoli Cells. Biotin tracer permeated throughout these tubules, demonstrating dysfunctional TJs. In hpg+tgFSH testes, claudin-3 was generally absent, but claudin-11 had redistributed basally toward the TJs, where function was variable. In hpg testes, DHT treatment stimulated the redistribution of claudin-11 protein toward the basal region of Sertoli Cells by Day 2, increased Cldn3 and Cldn11 mRNA expression, then induced the formation of functional TJs containing both proteins by Day 10. In hpg+tgFSH testes, TJ protein redistribution was accelerated and functional TJs formed by Day 2 of DHT treatment. We conclude that androgen stimulates initial Sertoli Cell TJ formation and function in mice, whereas FSH activity is insufficient alone, but augments androgen-induced TJ function.
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Is the Adult Sertoli Cell Terminally Differentiated
Biology of reproduction, 2012Co-Authors: Gerard A. Tarulli, Peter G Stanton, Sarah J MeachemAbstract:New data have challenged the convention that the adult Sertoli Cell population is fixed and unmodifiable. The Sertoli Cell has two distinct functions: 1) formation of the seminiferous cords and 2) provision of nutritional and structural support to developing germ Cells. For these to occur successfully, Sertoli Cells must undergo many maturational changes between fetal and adult life, the main switches occurring around puberty, including the loss of proliferative activity and the formation of the blood-testis barrier. Follicle-stimulating hormone plays a key role in promoting Sertoli Cell proliferation, while thyroid hormone inhibits proliferative activity in early postnatal life. Together these regulate the Sertoli-germ Cell complement and sperm output in adulthood. By puberty, the Sertoli Cell population is considered to be stable and unmodifiable by hormones. But there is mounting evidence that the size of the adult Sertoli Cell population and its maturational status is modifiable by hormones and that Sertoli Cells can gain proliferative ability in the spermatogenically disrupted hamster and human model. This new information demonstrates that the adult Sertoli Cell population, at least in the settings of testicular regression in the hamster and impaired fertility in humans in vivo and from mice and men in vitro, is not a terminally differentiated population. Data from the hamster now show that the adult Sertoli Cell population size is regulated by hormones. This creates exciting prospects for basic and clinical research in testis biology. The potential to replenish an adult Sertoli-germ Cell complement to normal in a setting of infertility may now be realized.
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Short title: A programmable Sertoli Cell Summary sentence: This review discusses the new developments in adult Sertoli Cell biology and the clinical potential of a programmable Sertoli Cell population
2012Co-Authors: Gerard A. Tarulli, Peter G Stanton, Sarah J MeachemAbstract:New data has challenged the convention that the adult Sertoli Cell population is fixed and unmodifiable. The Sertoli Cell has 2 distinct functions, i) formation of the seminiferous cords and ii) provision of nutritional and structural support to developing germ Cells. For these to occur successfully, Sertoli Cells must undergo many maturational changes between fetal and adult life, the main switches occurring around puberty, including the loss of proliferative activity and the formation of the blood testis barrier. Follicle stimulating hormone plays a key role in promoting Sertoli Cell proliferation while thyroid hormone inhibits proliferative activity in early postnatal
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Hormonal Regulation of Sertoli Cell Micro-RNAs at Spermiation
Endocrinology, 2011Co-Authors: Peter K. Nicholls, Craig A. Harrison, Kelly L. Walton, Liza O'donnell, Robert I Mclachlan, Peter G StantonAbstract:Hormonal regulation of micro-RNAs in the Sertoli Cell is predicted to contribute to changes in germ Cell:Sertoli Cell adhesion and the process of spermiation.
Bernard Jegou - One of the best experts on this subject based on the ideXlab platform.
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The Sertoli Cell in vivo and in vitro
Cell Biology and Toxicology, 1992Co-Authors: Bernard JegouAbstract:The Sertoli Cell extends from the basement membrane of the seminiferous tubule towards its lumen; it sends cytoplasmic processes which envelop different generations of germ Cells. The use of Sertoli Cell culture began to develop in 1975. To reduce germ Cell contamination immature animals are generally used as Sertoli Cell donors. Sertoli Cell mitosis essentially occurs in sexually immature testes in mammals; mitosis of these Cells is observed in vitro during a limited period of time. Sertoli Cells in vivo perform an impressive range of functions: structural support of the seminiferous epithelium, displacement of germ Cells and release of sperm; formation of the Sertoli Cell blood-testis barrier; secretion of factors and nutrition of germ Cells; phagocytosis of degenerating germ Cells and of germ Cell materials. Some of the Sertoli Cell functions can be studied in vitro. The recent development of Sertoli Cell culture on permeable supports (with or without extraCellular matrix) has resulted in progress in understanding the vectorial secretion of several Sertoli Cell markers. In addition to FSH and testosterone, several other humoral factors are known to influence Sertoli Cell function. Furthermore, myoid Cells bordering the tubules as well as germ Cells are capable of regulating Sertoli Cell activity. Sertoli Cells are the most widely used testicular Cells for in vitro toxicology . The testis is highly vulnerable to xenobiotics and radiations, yet the number of studies undertaken in this field is insufficient and should be drastically increased.
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Spermatids are regulators of Sertoli Cell function.
Annals of the New York Academy of Sciences, 1991Co-Authors: Bernard JegouAbstract:Spermatids are major regulators of Sertoli Cell function. Specific anatomical structures exist between spermatids and Sertoli Cells. Their nature evolves during spermiogenesis and they are essential mediators in the interaction between these two Cell types. Spermatids play a crucial role in Sertoli Cell gene expression and secretory function at different ages. Early spermatid effect is partly mediated through the secretion of soluble factor(s). The influence of late spermatids on Sertoli Cell secretion in the adult testis is conserved throughout evolution and may be mediated via their implication in the conformational changes on Sertoli Cells that occur during spermatogenesis and through phagocytosis of the residual bodies.
Paul S. Cooke - One of the best experts on this subject based on the ideXlab platform.
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Understanding the role of thyroid hormone in Sertoli Cell development: a mechanistic hypothesis
Cell and Tissue Research, 2005Co-Authors: Denise R. Holsberger, Paul S. CookeAbstract:More than a decade of research has shown that Sertoli Cell proliferation is regulated by thyroid hormone. Neonatal hypothyroidism lengthens the period of Sertoli Cell proliferation, leading to increases in Sertoli Cell number, testis weight, and daily sperm production (DSP) when euthyroidism is re-established. In contrast, the neonatal Sertoli Cell proliferative period is shortened under hyperthyroid conditions, but the mechanism by which thyroid hormone is able to negatively regulate Sertoli Cell proliferation has been unclear. Recent progress in the understanding of the Cell cycle has provided the opportunity to dissect the molecular targets responsible for thyroid-hormone-mediated effects on Sertoli Cell proliferation. In this review, we discuss recent results indicating a critical role for the cyclin-dependent kinase inhibitors (CDKI) p27^Kip1 and p21^Cip1 in establishing Sertoli Cell number, testis weight, and DSP, and the ability of thyroid hormone to modulate these CDKIs. Based on these recent results, we propose a working hypothesis for the way in which thyroid hormone regulates the withdrawal of the Cell cycle by controlling CDKI degradation. Finally, although Sertoli Cells have been shown to have two biologically active thyroid hormone receptor (TR) isoforms, TRα1 and TRβ1, experiments with transgenic mice lacking TRα or TRβ illustrate that only one TR mediates thyroid hormone effects in neonatal Sertoli Cells. Although significant gaps in our knowledge still remain, advances have been made toward appreciation of the molecular sequence of events that occur when thyroid hormone stimulates Sertoli Cell maturation.
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Thyroid Hormone Regulation of Sertoli Cell Development
Sertoli Cell Biology, 2005Co-Authors: Paul S. Cooke, Denise R. Holsberger, Luiz R. FrançaAbstract:This chapter discusses the mechanism through which thyroid hormone regulates Sertoli Cell development. Thyroid hormone plays a key role in Sertoli Cell maturation, and in this capacity promotes both cessation of Sertoli Cell proliferation and the key developmental changes that allow Sertoli Cells to support germ Cell development. Thyroid hormone treatment induces changes in various secretory proteins indicating that thyroid hormone could have significant functional effects on young Sertoli Cells. Early hypothyroidism inhibits testicular growth, germ Cell maturation, seminiferous tubule lumen formation, and other developmental events. However, neonatal hypothyroidism in rats, followed by a subsequent recovery to euthyroidism, produced unexpected and unprecedented increases in testis size and daily sperm production (DSP) during adulthood. The induction of hypothyroidism allows extended Sertoli Cell proliferation and produces an increased pool of Sertoli Cells despite its immediate inhibitory effects on germ Cell development and testis growth. When euthyroidism is restored, Sertoli Cell differentiation occurs and these Cells become capable of supporting full spermatogenesis. The increased Sertoli Cell population then results in increased numbers of germ Cells, probably due to the increased capacity of the larger Sertoli Cell population to support germ Cell development.
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Neonatal Hypothyroidism Causes Delayed Sertoli Cell Maturation in Rats Treated With Propylthiouracil: Evidence That the Sertoli Cell Controls Testis Growth
The Anatomical record, 1995Co-Authors: Luiz R. França, Rex A. Hess, Paul S. Cooke, Lonnie D. RussellAbstract:Background: The testes of rats treated neonatally with propylthiouracil (PTU) grow to almost twice their normal size. The cause of testicular enlargement has been suggested to be the result of delayed maturation of Sertoli Cells, allowing Sertoli Cell division to occur beyond the 15th postnatal day, the commonly recognized cutoff date for Sertoli Cell divisions. It has been shown that an increased population of Sertoli Cells in postnatal development supports increased numbers of germ Cells in adult animals. After examining developing rats treated neonatally with PTU, we hypothesized that an approximate 10-day delay in maturation was occurring and proceeded to test this hypothesis experimentally. Thus the purpose of this report was to determine if a 10-day delay in maturation could explain the increased numbers of Sertoli Cells and increased testis size in PTU-treated animals. Methods: Both control animals and animals treated neonatally with PTU N = 5/group were sacrificed at 15 and 25 days of age and prepared for electron microscopy. Results: Micrographs show and morphometric ultrastructural analysis of numerous parameters demonstrated at the 95% probability level that Sertoli Cells from 25-day-old PTU animals are not different in size and most constituents (volume and surface area) from 15-day-old control animals and are less mature than 25-day-old control animals. Mitosis of Sertoli Cells was observed in PTU-treated animals in 25-day-old animals but not in agematched controls. The number of Sertoli Cells in 25-day-old PTU-treated animals is significantly increased over age-matched controls. Micrographs show the presence of immature Sertoli Cell nuclei in 25-day-old animals receiving PTU as well as increased germ Cell degeneration in this group. Sertoli Cell tight junction formation is also delayed in PTU-treated animals as compared with controls. Conclusions: Together, the data show that delayed maturation of Sertoli Cells occurs in treated animals that corresponds to a minimum of 10 developmental days. In the immature state, Sertoli Cells continue to divide. Data presented herein and published data related to PTU treatment indicate that delayed maturation of the Sertoli Cell results in delayed maturation and proliferation of other testicular Cell types. From this and from published data, the hypothesis is presented that the Sertoli Cell is responsible for the overall control of testis development. © 1995 Wiley-Liss, Inc.
Diane Rebourcet - One of the best experts on this subject based on the ideXlab platform.
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Identification of Sertoli Cell-specific transcripts in the mouse testis and the role of FSH and androgen in the control of Sertoli Cell activity
BMC genomics, 2017Co-Authors: Ugo Soffientini, Lee B. Smith, Diane Rebourcet, M.h. Abel, S Lee, G Hamilton, Paul Fowler, Peter J. O'shaughnessyAbstract:The Sertoli Cells act to induce testis differentiation and subsequent development in fetal and post-natal life which makes them key to an understanding of testis biology. As a major step towards characterisation of factors involved in Sertoli Cell function we have identified Sertoli Cell-specific transcripts in the mouse testis and have used the data to identify Sertoli Cell-specific transcripts altered in mice lacking follicle-stimulating hormone receptors (FSHRKO) and/or androgen receptors (AR) in the Sertoli Cells (SCARKO). Adult iDTR mice were injected with busulfan to ablate the germ Cells and 50 days later they were treated with diphtheria toxin (DTX) to ablate the Sertoli Cells. RNAseq carried out on testes from control, busulfan-treated and busulfan + DTX-treated mice identified 701 Sertoli-specific transcripts and 4302 germ Cell-specific transcripts. This data was mapped against results from microarrays using testicular mRNA from 20 day-old FSHRKO, SCARKO and FSHRKO.SCARKO mice. Results show that of the 534 Sertoli Cell-specific transcripts present on the gene chips, 85% were altered in the FSHRKO mice and 94% in the SCARKO mice (mostly reduced in both cases). In the FSHRKO.SCARKO mice additive or synergistic effects were seen for most transcripts. Age-dependent studies on a selected number of Sertoli Cell-specific transcripts, showed that the marked effects in the FSHRKO at 20 days had largely disappeared by adulthood although synergistic effects of FSHR and AR knockout were seen. These studies have identified the Sertoli Cell-specific transcriptome in the mouse testis and have shown that most genes in the transcriptome are FSH- and androgen-dependent at puberty although the importance of FSH diminishes towards adulthood.
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Sertoli Cell number defines and predicts germ and leydig Cell population sizes in the adult mouse testis
Endocrinology, 2017Co-Authors: Diane Rebourcet, Annalucia Darbey, Ana Monteiro, Ugo Soffientini, Yi Ting Tsai, Ian Handel, Jeanluc Pitetti, Serge Nef, Lee B. SmithAbstract:Sertoli Cells regulate differentiation and development of the testis and are essential for maintaining adult testis function. To model the effects of dysregulating Sertoli Cell number during development or aging, we have used acute diphtheria toxin-mediated Cell ablation to reduce Sertoli Cell population size. Results show that the size of the Sertoli Cell population that forms during development determines the number of germ Cells and Leydig Cells that will be present in the adult testis. Similarly, the number of germ Cells and Leydig Cells that can be maintained in the adult depends directly on the size of the adult Sertoli Cell population. Finally, we have used linear modeling to generate predictive models of testis Cell composition during development and in the adult based on the size of the Sertoli Cell population. This study shows that at all ages the size of the Sertoli Cell population is predictive of resulting testicular Cell composition. A reduction in Sertoli Cell number/proliferation at any age will therefore lead to a proportional decrease in germ Cell and Leydig Cell numbers, with likely consequential effects on fertility and health.
Barry R. Zirkin - One of the best experts on this subject based on the ideXlab platform.
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an ex vivo analysis of Sertoli Cell actin dynamics following gonadotropic hormone withdrawal
Journal of Andrology, 2004Co-Authors: Matthew D Show, Matthew D Anway, Barry R. ZirkinAbstract:ABSTRACT: The receptors for the steroid hormone testosterone and the peptide hormone follicle-stimulating hormone are localized to the somatic Sertoli Cell in the seminiferous epithelium. In the rat, prolonged gonadotrophic hormone withdrawal has been shown to result in substantial germ Cell apoptosis. Previous studies have shown that, coincident with the loss of germ Cells following hypophysectomy, the actin cytoskeleton of the Sertoli Cell becomes disorganized and diffuse throughout the Cell's cytoplasm. The molecular mechanisms that govern Sertoli Cell actin filament dynamics in response to the loss of gonadotrophic hormones remain undefined. It was therefore hypothesized that hypophysectomy brings about a decrease in the amount of polymerized actin (F-actin) within the Sertoli Cell and that this decrease is associated with changes in the expression of genes known to govern Sertoli actin dynamics. To this end, Sertoli Cells were isolated from adult control and hypophysectomized rats. Sertoli Cells from hypophysectomized rats were found to contain significantly less (72%) F-actin relative to untreated controls, although overall, β-actin protein and mRNA expression remained constant. The expression levels of genes known to directly influence the amount of F-actin in Cells were then examined by Northern blot analysis. Cofilin and profilin I gene expression was unaffected by hypophysectomy, whereas the expression of profilin II and espin both decreased significantly (47% and 42%, respectively). Taken together, these results suggest that, following hypophysectomy, the actin cytoskeleton of the Sertoli Cell shifts to a predominantly depolymerized state, perhaps in part because of decreases in profilin II and espin gene products.
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reduced intratesticular testosterone concentration alters the polymerization state of the Sertoli Cell intermediate filament cytoskeleton by degradation of vimentin
Endocrinology, 2003Co-Authors: Matthew D Show, Matthew D Anway, Janet Folmer, Barry R. ZirkinAbstract:The Sertoli Cell intermediate filament cytoskeleton is composed of the type III family member vimentin. The distribution of Sertoli Cell vimentin varies with the stage of spermatogenesis, with shortening of the filaments at stages VII-VIII, the stages of spermiation. Experimental reduction in intratesticular testosterone (T) concentration also results in the sloughing of advanced spermatids from the Sertoli Cells, as well as in the apoptotic death of spermatocytes. We hypothesized that alteration of the distribution of Sertoli Cell vimentin might play a role in the loss of germ Cells that occurs in response to reduced intratesticular T. To test this hypothesis, intratesticular T was reduced by implanting LH-suppressive SILASTIC brand capsules containing T and estradiol into adult rats for 8 wk. Immunohistochemical analyses revealed that, in response to the implants, the vimentin cytoskeleton collapsed around the Sertoli Cell nuclei at all stages of the cycle, losing the extensive branching and structure normally seen at most stages of the cycle. Western blots of isolated Sertoli Cells revealed that protein levels did not differ significantly between control and T- and estradiol-treated rats. However, Sertoli Cell fractions containing the vimentin monomer revealed that vimentin was cleaved into four to five fragments in Sertoli Cells in response to the implants, suggestive of proteolysis. These results indicate that, in response to reduced intratesticular T, the vimentin cytoskeleton of the Sertoli Cell collapses to a perinuclear localization, and suggest that this collapse is associated with, and perhaps caused by, the degradation of the vimentin monomer rather than by loss of its expression.
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Immortalization and characterization of a Sertoli Cell line from the adult rat.
Biology of reproduction, 1995Co-Authors: Kenneth P. Roberts, Partha P. Banerjee, John W.m. Tindall, Barry R. ZirkinAbstract:To facilitate investigations of the regulation of adult Sertoli Cell function, we have established a Sertoli Cell line from sexually mature Sprague-Dawley rats. The Cells were immortalized with the temperature-sensitive mutant of the SV40 virus, tsA255. The tsA255 large T antigen is heat-labile and efficiently promotes propagation of Cells at 33°C (permissive temperature) but is inactive at 40C (nonpermissive temperature). The established clonal Sertoli Cell line (ASC-17D) proliferates indefinitely at the permissive temperature. However, within 48 h at the nonpermissive temperature, Cell proliferation ceases. ASC-17D Cells show positive staining with antibodies to cytokeratin and vimentin, consistent with the Sertoli Cell origin of these Cells. Transferrin and sulfated glycoprotein (SGP)-2 mRNAs were nearly undetectable in ASC-17D Cells cultured at the permissive temperature, but expression of both mRNAs was induced at the nonpermissive temperature. In contrast, SGP-1 was expressed equally at both the permissive and nonpermissive temperatures. There was no increase in either transferrin or SGP-2 with FSH or dibutyryl cAMP (db-cAMP) treatment at the permissive temperature or with FSH treatment at the nonpermissive temperature. However, the steady-state levels of both of these mRNAs were substantially increased in the presence of db-cAMP at the nonpermissive temperature. In contrast, SGP-1 mRNA was not affected by either FSH or db-cAMR These results suggest that the ASC-17D Cell line is derived from adult Sertoli Cells and may be useful for the study of adult Sertoli Cell function.
