scholarly journals Importance of the Androgen Receptor Signaling in Gene Transactivation and Transrepression for Pubertal Maturation of the Testis

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 861 ◽  
Author(s):  
Nadia Y. Edelsztein ◽  
Rodolfo A. Rey
Keyword(s):  
Androgen Receptor ◽  
Sertoli Cell ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Pubertal Development ◽  
Cell Maturation ◽  
Androgen Receptor Signaling ◽  
Tight Junction Formation ◽  
Germ Cell Differentiation ◽  
Junction Formation

Androgens are key for pubertal development of the mammalian testis, a phenomenon that is tightly linked to Sertoli cell maturation. In this review, we discuss how androgen signaling affects Sertoli cell function and morphology by concomitantly inhibiting some processes and promoting others that contribute jointly to the completion of spermatogenesis. We focus on the molecular mechanisms that underlie anti-Müllerian hormone (AMH) inhibition by androgens at puberty, as well as on the role androgens have on Sertoli cell tight junction formation and maintenance and, consequently, on its effect on proper germ cell differentiation and meiotic onset during spermatogenesis.

scholarly journals Importance of the Androgen Receptor Signalling in Gene Transactivation and Transrepression for Pubertal Maturation of the Testis

2019 ◽  
Author(s):  
Nadia Y. Edelsztein ◽  
Rodolfo A. Rey
Keyword(s):  
Androgen Receptor ◽  
Sertoli Cell ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Pubertal Development ◽  
Cell Maturation ◽  
Receptor Signalling ◽  
Tight Junction Formation ◽  
Germ Cell Differentiation ◽  
Junction Formation

Androgens are key for pubertal development of the mammalian testis, a phenomenon tightly linked to Sertoli cell maturation. In this review, we discuss how androgen signalling affects Sertoli cell function and morphology by concomitantly inhibiting some processes and promoting others that contribute jointly to the completion of spermatogenesis. We focus on the molecular mechanisms that underlie AMH inhibition by androgens at puberty, as well as on the role androgens have on Sertoli cell tight junction formation and maintenance and, consequently, on its effect on proper germ cell differentiation and meiotic onset during spermatogenesis.

scholarly journals Elevated expression of the Sertoli cell androgen receptor disrupts male fertility

2016 ◽  
Vol 311 (2) ◽  
pp. E396-E404 ◽  
Author(s):  
Rasmani Hazra ◽  
Dannielle Upton ◽  
Reena Desai ◽  
Omar Noori ◽  
Mark Jimenez ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Germ Cell ◽  
Sertoli Cell ◽  
Germ Cells ◽  
Male Fertility ◽  
Leydig Cells ◽  
Cell Function ◽  
Pubertal Development ◽  
Receptor Expression ◽  
Testis Size

Recently, we created a unique gain-of-function mouse model with Sertoli cell-specific transgenic androgen receptor expression (TgSCAR) showing that SCAR activity controls the synchronized postnatal development of somatic Sertoli and Leydig cells and meiotic-postmeiotic germ cells. Moderate TgSCAR (TgSCARm) expression reduced testis size but had no effect on male fertility. Here, we reveal that higher TgSCAR expression (TgSCARH) causes male infertility. Higher SCAR activity, shown by upregulated AR-dependent transcripts ( Rhox5, Spinw1), resulted in smaller adult TgSCARH testes (50% of normal) despite normal or elevated circulating and intratesticular testosterone levels. Unlike fertile TgSCARm males, testes of adult TgSCARH males exhibited focal regions of interstitial hypertrophy featuring immature adult Leydig cells and higher intratesticular dihydrotestosterone and 5α-androstane 3α,17β-diol levels that are normally associated with pubertal development. Mature TgSCARH testes also exhibited markedly reduced Sertoli cell numbers (70%), although meiotic and postmeiotic germ cell/Sertoli cell ratios were twofold higher than normal, suggesting that elevated TgSCAR activity supports excessive spermatogenic development. Concurrent with the higher germ cell load of TgSCARH Sertoli cells were increased levels of apoptotic germ cells in TgSCARH relative to TgSCARm testes. In addition, TgSCARH testes displayed unique morphological degeneration that featured accumulated cellular and spermatozoa clusters in dilated channels of rete testes, consistent with reduced epididymal sperm numbers. Our findings reveal for the first time that excessive Sertoli cell AR activity in mature testes can reach a level that disturbs Sertoli/germ cell homeostasis, impacts focal Leydig cell function, reduces sperm output, and disrupts male fertility.

scholarly journals Smad3 Dosage Determines Androgen Responsiveness and Sets the Pace of Postnatal Testis Development

Endocrinology ◽  
2011 ◽  
Vol 152 (5) ◽  
pp. 2076-2089 ◽  
Author(s):  
Catherine Itman ◽  
Chin Wong ◽  
Briony Hunyadi ◽  
Matthias Ernst ◽  
David A. Jans ◽  
...  
Keyword(s):  
Germ Cell ◽  
Sertoli Cell ◽  
Pubertal Development ◽  
Cell Development ◽  
Cell Maturation ◽  
Developmentally Regulated ◽  
Testis Development ◽  
Essentially Normal ◽  
Endocrine Factors ◽  
Immature Cells

The establishment and maturation of the testicular Sertoli cell population underpins adult male fertility. These events are influenced by hormones and endocrine factors, including FSH, testosterone and activin. Activin A has developmentally regulated effects on Sertoli cells, enhancing proliferation of immature cells and later promoting postmitotic maturation. These differential responses correlate with altered mothers against decapentaplegic (SMAD)-2/3 signaling: immature cells signal via SMAD3, whereas postmitotic cells use both SMAD2 and SMAD3. This study examined the contribution of SMAD3 to postnatal mouse testis development. We show that SMAD3 production and subcellular localization are highly regulated and, through histological and molecular analyses, identify effects of altered Smad3 dosage on Sertoli and germ cell development. Smad3+/− and Smad3−/− mice had smaller testes at 7 d postpartum, but this was not sustained into adulthood. Juvenile and adult serum FSH levels were unaffected by genotype. Smad3-null mice displayed delayed Sertoli cell maturation and had reduced expression of androgen receptor (AR), androgen-regulated transcripts, and Smad2, whereas germ cell and Leydig cell development were essentially normal. This contrasted remarkably with advanced Sertoli and germ cell maturation and increased expression of AR and androgen-regulated transcripts in Smad3+/− mice. In addition, SMAD3 was down-regulated during testis development and testosterone up-regulated Smad2, but not Smad3, in the TM4 Sertoli cell line. Collectively these data reveal that appropriate SMAD3-mediated signaling drives normal Sertoli cell proliferation, androgen responsiveness, and maturation and influences the pace of the first wave of spermatogenesis, providing new clues to causes of altered pubertal development in boys.

035. THE ROLE OF THE SERTOLI CELL IN REGULATING SPERMATOGENESIS, IMMUNE RESPONSES AND INFLAMMATORY DISEASE: MULTIPLE FUNCTIONS, COMMON MECHANISMS?

2009 ◽  
Vol 21 (9) ◽  
pp. 8
Author(s):  
M. P. Hedger ◽  
J. A. Muir ◽  
W. R. Winnall
Keyword(s):  
Sertoli Cell ◽  
Inflammatory Cytokines ◽  
Cell Function ◽  
Inhibitory Effect ◽  
Inhibitory Effects ◽  
Tight Junction Formation ◽  
Interleukin 1Α ◽  
Factor Α ◽  
Necrosis Factor

There is increasing evidence that the Sertoli cell, in addition to modulating responses to direct antigenic challenges (eg. intratesticular allografts), is central to the response of the testis to inflammation and infection. Systemic inflammation exerts an inhibitory effect on spermatogenesis, which has been attributed to the effects of fever, vascular disturbances, or loss of androgenic support. However, recent studies point to more direct effects of inflammation on spermatogenesis. The discovery that Sertoli cells express Toll-like receptors (TLR), and react to TLR ligands by producing inflammatory cytokines and other mediators, provides a mechanism to account for this direct inhibition. Moreover, the pattern of cytokines produced by the Sertoli cell during inflammation is highly characteristic. For example, when stimulated with TLR ligands the Sertoli cell produces the pro-inflammatory cytokines, interleukin-1α (IL1α) and IL6, and the regulatory cytokine, activin A, but does not produce IL1β and tumour necrosis factor-α, which are major pro-inflammatory products of activated macrophages. The disruptive effects of inflammation on spermatogenesis may be attributed to the elevated production of these cytokines, all of which have stimulatory or inhibitory effects on germ cell mitosis, meiosis and apoptosis and Sertoli cell tight junction formation, In addition, activation of TLR/IL1 mediated inflammatory pathways in the Sertoli cell inhibits its ability to respond to its principal trophic hormone, follicle-stimulating hormone. Studies on the regulation of these interactions will further establish the role of the Sertoli cell in inflammation and infection. However, such studies also have important implications for normal Sertoli cell function, as TLRs can respond to endogenous ligands as well. Consequently, the Sertoli cell may be viewed as a sentinel cell, supporting and protecting spermatogenesis when conditions are optimal, but rapidly shutting down spermatogenesis in the presence of infection or illness. Intriguingly, these apparently disparate roles appear to involve common inflammation-related mechanisms.

scholarly journals Abnormalities of Germ Cell Maturation and Sertoli Cell Cytoskeleton in Androgen Receptor 113 CAG Knock-In Mice Reveal Toxic Effects of the Mutant Protein

2006 ◽  
Vol 168 (1) ◽  
pp. 195-204 ◽  
Author(s):  
Zhigang Yu ◽  
Nahid Dadgar ◽  
Megan Albertelli ◽  
Arno Scheller ◽  
Roger L. Albin ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Germ Cell ◽  
Sertoli Cell ◽  
Toxic Effects ◽  
Cell Maturation ◽  
Mutant Protein ◽  
Cell Cytoskeleton

scholarly journals Maturation of Testicular Tissue from Infant Monkeys after Xenografting into Mice

Endocrinology ◽  
2008 ◽  
Vol 149 (10) ◽  
pp. 5288-5296 ◽  
Author(s):  
Rahul Rathi ◽  
Wenxian Zeng ◽  
Susan Megee ◽  
Alan Conley ◽  
Stuart Meyers ◽  
...  
Keyword(s):  
Germ Cell ◽  
Somatic Cell ◽  
Sertoli Cell ◽  
Rhesus Monkeys ◽  
Testicular Tissue ◽  
Cell Maturation ◽  
Nuclear Antigen ◽  
Donor Age ◽  
Germ Cell Differentiation ◽  
Testis Tissue

In juvenile monkeys, precocious puberty can be induced by administration of gonadotropins resulting in testicular somatic cell maturation and germ cell differentiation. It is, however, unknown whether testicular maturation can also be induced in younger monkeys. Here we used testis tissue xenografting to investigate whether infant monkey testis tissue will undergo somatic cell maturation and/or spermatogenesis in response to endogenous adult mouse gonadotropins or exogenous gonadotropins. Testicular tissue pieces from 3- and 6-month-old rhesus monkeys were grafted to immunodeficient, castrated mice. Recipient mice were either left untreated or treated with pregnant mare serum gonadotropin and/or human chorionic gonadotropin twice weekly and were killed 28 weeks after grafting. Testicular maturation in grafted tissue was assessed based on morphology and the most advanced germ cell type present and by immunohistochemistry for expression of proliferating cell nuclear antigen, Mullerian-inhibiting substance, and androgen receptor. Testis grafts, irrespective of donor age or treatment, contained fewer germ cells than donor tissue. Grafts from 6-month-old donors showed tubular expansion with increased seminiferous tubule diameter and lumen formation, whereas those harvested from gonadotropin-treated mice contained elongated spermatids. Grafts from 3-month-old donors recovered from gonadotropin-treated mice contained pachytene spermatocytes, whereas those recovered from untreated mice showed only slight tubular expansion. Immunohistochemistry revealed that exposure to exogenous gonadotropins supported Sertoli cell maturation, irrespective of donor age. These results indicate that sustained gonadotropin stimulation of immature (<12 months old) monkey testis supports Sertoli cell maturation, thereby terminating the unresponsive phase of the germinal epithelium and allowing complete spermatogenesis in testis tissue from infant rhesus monkeys.

scholarly journals Interplay between the androgen receptor signaling axis and microRNAs in prostate cancer

2019 ◽  
Vol 26 (5) ◽  
pp. R237-R257 ◽  
Author(s):  
Rayzel C Fernandes ◽  
Theresa E Hickey ◽  
Wayne D Tilley ◽  
Luke A Selth
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Transcription Factor ◽  
Androgen Receptor ◽  
Molecular Mechanisms ◽  
Clinical Applications ◽  
Cancer Growth ◽  
Androgen Receptor Signaling ◽  
Resistance To Therapy ◽  
Signaling Axis

The androgen receptor (AR) is a ligand-activated transcription factor that drives prostate cancer. Since therapies that target the AR are the mainstay treatment for men with metastatic disease, it is essential to understand the molecular mechanisms underlying oncogenic AR signaling in the prostate. miRNAs are small, non-coding regulators of gene expression that play a key role in prostate cancer and are increasingly recognized as targets or modulators of the AR signaling axis. In this review, we examine the regulation of AR signaling by miRNAs and vice versa and discuss how this interplay influences prostate cancer growth, metastasis and resistance to therapy. Finally, we explore the potential clinical applications of miRNAs implicated in the regulation of AR signaling in this prevalent hormone-driven disease.

Sertoli Cell-Specific Modification of The Androgen Receptor DNA-Binding Domain Disrupts Sertoli Cell Function and Completion of Spermatogenesis.

2008 ◽  
Vol 78 (Suppl_1) ◽  
pp. 54-55
Author(s):  
Charles M. Allan ◽  
Patrick Lim ◽  
Mark Jimenez ◽  
Jennifer Spaliviero ◽  
Kirsten McTavish ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Dna Binding ◽  
Sertoli Cell ◽  
Cell Function ◽  
Binding Domain ◽  
Dna Binding Domain ◽  
Specific Modification

scholarly journals Hydrocortisone induces changes in gene expression and differentiation in immature human enterocytes

2011 ◽  
Vol 300 (3) ◽  
pp. G425-G432 ◽  
Author(s):  
Lei Lu ◽  
Tiantian Li ◽  
Graham Williams ◽  
Elizabeth Petit ◽  
Mark Borowsky ◽  
...  
Keyword(s):  
Gene Expression ◽  
Epithelial Cell ◽  
Intestinal Epithelial Cell ◽  
Molecular Mechanisms ◽  
Cell Maturation ◽  
Epithelial Cell Line ◽  
Intestinal Epithelial ◽  
Tight Junction Formation ◽  
Expression Of Genes ◽  
Small Intestinal

It is known that functional maturation of the small intestine occurring during the weaning period is facilitated by glucocorticoids (such as hydrocortisone, HC), including an increased expression of digestive hydrolases. However, the molecular mechanisms are not well understood, particularly in the human gut. Here we report a microarray analysis of HC-induced changes in gene expression in H4 cells (a well-characterized human fetal small intestinal epithelial cell line). This study identified a large number of HC-regulated genes, some involved in metabolism, cell cycle regulation, cell-cell or cell-extracellular matrix communication. HC also regulates the expression of genes important for cell maturation such as development of cell polarity, tight junction formation, and interactions with extracellular matrices. Using human small intestinal xenografts, we also show that HC can regulate the expression of genes important for intestinal epithelial cell maturation. Our dataset may serve as a useful resource for understanding and dissecting the molecular mechanisms of intestinal epithelial cell maturation.

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