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.

scholarly journals Morphological changes of Sertoli cells during the male reproductive cycle of the teleost Piaractus mesopotamicus (Holmberg, 1887)

2005 ◽  
Vol 65 (2) ◽  
pp. 241-249 ◽  
Author(s):  
C. Cruz-Landim ◽  
F. C. Abdalla ◽  
M. A. Cruz-Höfling
Keyword(s):  
Germ Cell ◽  
Sertoli Cell ◽  
Reproductive Cycle ◽  
Sertoli Cells ◽  
Morphological Changes ◽  
Cell Development ◽  
Cell Maturation ◽  
Ultrastructural Changes ◽  
Piaractus Mesopotamicus

An investigation of the histological and ultrastructural changes of Sertoli cells during the male reproductive cycle in Piaractus mesopotamicus was made. The results showed that the Sertoli cell development is closely related with germ cell maturation. Therefore, these cells may have some role in germ cell maturation during the reproductive cycle of this species, whether in forming a tissue framework for the developing spermatogenic cysts, aiding in testes reorganization for a new reproductive cycle, in addition to other possible functions discussed in the text.

232. Developmentally regulated activin A signal transduction by Sertoli cells is required for normal mouse testis development

2008 ◽  
Vol 20 (9) ◽  
pp. 32
Author(s):  
C. M. Itman ◽  
C. Small ◽  
M. Griswold ◽  
A. K. Nagaraja ◽  
M. M. Matzuk ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Sertoli Cell ◽  
Sertoli Cells ◽  
Normal Mouse ◽  
Mouse Testis ◽  
Nuclear Accumulation ◽  
Developmentally Regulated ◽  
Testis Development ◽  
Differentiated Cells ◽  
Immature Cells

Activin A, a TGF-β superfamily ligand, is critical for normal mouse testis development and quantitatively normal sperm production. Testicular activin production changes during development, being substantially higher in the immature testis relative to the adult [1, 2]. Activin influences the Sertoli cell, the nurse cell to developing sperm, enhancing proliferation during its immature phase, but not following terminal differentiation [3]. In the Inha−/− mouse, chronic excessive activin production results in Sertoli cell-derived tumours [4] whereas reduced activin bioactivity, in the InhbaBK/BK mouse, delays fertility [5]. Activin signals are transduced by the phosphorylation and nuclear accumulation of the transcription factors SMAD2 and SMAD3. By comparing activin signal transduction in immature v. terminally differentiated Sertoli cells, using quantitative confocal microscopy and western blot analysis of total and phosphorylated SMAD2 and SMAD3, we discovered that mouse Sertoli cells exhibit developmentally regulated activin responses. Activin induces nuclear accumulation of SMAD3, but not SMAD2, in immature cells, although both proteins are phosphorylated. In contrast, terminally differentiated cells exhibit nuclear accumulation of both SMAD2 and SMAD3. We observed that this shift coincides with decreased SMAD3 production at puberty and changes in FSH-induced Smad transcription, which favours Smad3 in immature cells but promotes Smad2 synthesis in terminally differentiated cells. Furthermore, whereas removal of SMAD3 from the Inha−/− mouse rescues the tumour phenotype [6], we demonstrated that insufficient SMAD3 production impairs testis growth. We hypothesised that this developmentally regulated SMAD utilisation drives specific transcriptional outcomes. Using microarray and quantitative PCR, we identified novel activin target genes displaying developmental stage-specific expression patterns coinciding with differential SMAD usage, including Gja1 and Serpina5 which are required for male fertility. These mRNAs are also modulated in vivo, increased 1.5–2 fold in Inha−/− testes and decreased by half in InhbaBK/BK testes, confirming that normal testis development requires carefully regulated activin production and responsiveness. (1) Buzzard J et al. 2004. Endocrinology 145(7): 3532–3541 (2) Barakat et al. 2008. Reproduction 2008 Epub ahead of print (3) Boitani C et al. 1995. Endocrinology 136(12): 4538–4544 (4) Matzuk M et al. 1992. Nature 360: 313–319 (5) Brown C et al. 2000. Nature Genetics 25(4): 453–457 (6) Li Q et al. 2007. Molecular Endocrinology 21(10: 2472–2486

Molecular mechanisms involved in Sertoli cell adaptation to glucose deprivation

2009 ◽  
Vol 297 (4) ◽  
pp. E907-E914 ◽  
Author(s):  
María F. Riera ◽  
María N. Galardo ◽  
Eliana H. Pellizzari ◽  
Silvina B. Meroni ◽  
Selva B. Cigorraga
Keyword(s):  
Germ Cell ◽  
Glucose Uptake ◽  
Sertoli Cell ◽  
Sertoli Cells ◽  
Molecular Mechanisms ◽  
Lactate Concentration ◽  
Glucose Deprivation ◽  
Cell Development ◽  
Germ Cell Development ◽  
Glucose Levels

Sertoli cells provide the physical support and the necessary environment for germ cell development. Among the products secreted by Sertoli cells, lactate, the preferred energy substrate for spermatocytes and spermatids, is present. Considering the essential role of lactate on germ cell metabolism, it is supposed that Sertoli cells must ensure its production even in adverse conditions, such as those that would result from a decrease in glucose levels in the extracellular milieu. The aim of the present study was to investigate 1) a possible effect of glucose deprivation on glucose uptake and on the expression of glucose transporters in rat Sertoli cells and 2) the participation of different signal transduction pathways in the above-mentioned regulation. Results obtained show that decreasing glucose levels in Sertoli cell culture medium provokes 1) an increase in glucose uptake accompanied by only a slight decrease in lactate production, 2) an increase in GLUT1 and a decrease in GLUT3 expression, and 3) an activation of AMP-activated protein kinase (AMPK)-, phosphatidylinositol 3-kinase (PI3K)/PKB-, and p38 MAPK-dependent pathways. Additionally, by using specific inhibitors of these pathways, a possible participation of AMPK- and p38MAPK-dependent pathways in the regulation of glucose uptake and GLUT1 expression is shown. These results suggest that Sertoli cells adapt to conditions of glucose deprivation to ensure an adequate lactate concentration in the microenvironment where germ cell development occurs.

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.

220 EFFECTS OF FOLLICLE-STIMULATING HORMONE AND 6-N-PROPYL-2-THIOURACIL ON BOAR SPERMATOGENESIS

2008 ◽  
Vol 20 (1) ◽  
pp. 189
Author(s):  
J. Baldrighi ◽  
W. Averhart ◽  
M. Mello ◽  
J. Ford ◽  
L. Franca ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Germ Cell ◽  
Sertoli Cell ◽  
Sertoli Cells ◽  
Sperm Cell ◽  
Follicle Stimulating Hormone ◽  
Cell Development ◽  
Seminiferous Tubules ◽  
Post Surgery ◽  
Stimulating Hormone

Currently, swine biotechnologies related to reproduction increase considerably. Investments are made in order to improve the reproductive rates and performance of breeding stock. Understanding the physiology of spermatogenesis will help increase sperm production and improve boar efficiency. Sertoli cells are the only somatic cells present in the seminiferous tubules. Their function is to guarantee proper sperm formation and maturation. Each Sertoli cell is responsible for nursing a finite number of spermatogonia. At puberty, Sertoli cell maturation and lumen formation have occurred within the seminiferous tubules and germ cells have proliferated rapidly followed by the onset of spermatogenesis. At least two hormones are known to play a role in Sertoli cell proliferation and maturation: follicle-stimulating hormone (FSH) and thyroid hormone. FSH secretion has been assumed to be the stimulus for proliferation. The thyroid hormone is responsible for normal postnatal growth and development. Alterations in thyroid activity have frequently been associated with changes in male reproductive functions, since hypothyroidism, induced with 6-N-propyl-2-thiouracil (PTU) soon after birth, is associated with a marked delay in sexual maturation and development. The goal of this study was to report the effect of FSH and PTU on the stages of sperm cell development of young pigs. Six piglets of 1, 7, 14, 25, and 55 days of age were castrated and their testes were sectioned to grafts of 5 mm3. The grafts were then transplanted subcutaneously into the dorsum of 12 castrated nude mice per age group. Two days post-surgery mice were randomly assigned to one of four treatment groups: control, FSH (5 IU rFSH), PTU (0.015% solution), and FSH + PTU. Following 14 days of treatment, testicular tissue pieces were allowed to grow for 2 additional weeks. Tissues were then harvested, immersion-fixed in neutral buffered formalin, and embedded in paraffin. Five-micron-thick sections were stained using hematoxylin and eosin. Slides were evaluated under light microscopy and the oldest germ cell type present in each section was recorded. Germ cell types were recorded as spermatogonium, spermatocyte, early spermatid, and late spermatid. Statistical differences between all groups were detected using paired Student t-tests. There were no differences noted between control groups and those treated with PTU or FSH alone. No effect concerning age of castration on grafts development was observed. There was a slightly significant increase (P = 0.05) in the number of spermatocytes observed in the groups treated with FSH+PTU. These data suggest that there is a potential synergistic effect of FSH and PTU on sperm cell development. Based on these results, further studies need to be performed to completely understand the effect of these two hormones on Sertoli cells.

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 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 Regulation of Germ Cell and Sertoli Cell Development by Activin, Follistatin, and FSH

2000 ◽  
Vol 220 (2) ◽  
pp. 225-237 ◽  
Author(s):  
Terri Meehan ◽  
Stefan Schlatt ◽  
Moira K. O'Bryan ◽  
David M. de Kretser ◽  
Kate Lakoski Loveland
Keyword(s):  
Germ Cell ◽  
Sertoli Cell ◽  
Cell Development

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.

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