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

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.

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Molecular mechanisms involved in Sertoli cell adaptation to glucose deprivation

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00235.2009 ◽

2009 ◽

Vol 297 (4) ◽

pp. E907-E914 ◽

Cited By ~ 50

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.

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

Brazilian Journal of Biology ◽

10.1590/s1519-69842005000200007 ◽

2005 ◽

Vol 65 (2) ◽

pp. 241-249 ◽

Cited By ~ 3

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.

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

Reproduction Fertility and Development ◽

10.1071/rdv20n1ab220 ◽

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.

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Retinoblastoma Protein pRb Is Required in Sertoli Cell To Support Male Germ Cell Development.

10.1210/endo-meetings.2010.part3.p7.p3-343 ◽

2010 ◽

pp. P3-343-P3-343

Author(s):

S Bourguiba ◽

E Rotgers ◽

A Rivero-Muller ◽

M Nurmio ◽

M Parvinen ◽

...

Keyword(s):

Germ Cell ◽

Sertoli Cell ◽

Retinoblastoma Protein ◽

Cell Development ◽

Male Germ Cell ◽

Germ Cell Development

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Transgenic mutant D567G but not wild-type human FSH receptor overexpression provides FSH-independent and promiscuous glycoprotein hormone Sertoli cell signaling

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.90941.2008 ◽

2009 ◽

Vol 296 (5) ◽

pp. E1022-E1028 ◽

Cited By ~ 16

Author(s):

Charles M. Allan ◽

Patrick Lim ◽

Mathew Robson ◽

Jenny Spaliviero ◽

David J. Handelsman

Keyword(s):

Germ Cell ◽

Sertoli Cell ◽

Sertoli Cells ◽

Cell Development ◽

Fsh Receptor ◽

Wild Type ◽

Glycoprotein Hormone ◽

Germ Cell Development ◽

Camp Levels

We have characterized the in vivo actions of human wild-type FSH receptor (FSHR) overexpressed in Sertoli cells of transgenic (Tg) mice ( TgFSHRwt) compared with transgenic overexpression of the human activated mutant FSHR*D567G ( TgFSHR*D567G). Testicular TgFSHRwt expression significantly elevated specific FSH binding (>2-fold, P < 0.01) relative to nontransgenic testes, similar to increased FSH binding in TgFSHR*D567G testes. Isolated TgFSHRwt Sertoli cells exhibited higher FSH-stimulated cAMP levels compared with non- Tg or TgFSHR*D567G cells but did not display the elevated FSH-independent basal cAMP levels found in TgFSHR*D567G Sertoli cells. Furthermore, Sertoli cell overexpression of TgFSHR*D567G but not TgFSHRwt allowed promiscuous cAMP responses to human chorionic gonadotropin (300 IU/ml) and TSH (30 mIU/ml), demonstrating increased constitutive signaling and altered glycoprotein hormone specificity via the intracellular D567G substitution rather than FSHR overexpression. Despite elevating Sertoli cell FSH sensitivity, overexpression of TgFSHRwt had no detectable effect upon normal testis function and did not stimulate Sertoli and germ cell development in testes of gonadotropin-deficient hypogonadal ( hpg) mice, in contrast to the increased meiotic and postmeiotic germ cell development in TgFSHR*D567G hpg testes. Increased steroidogenic potential of TgFSHR*D567G hpg testes was demonstrated by elevated Cyp11a1 and Star expression, which was not detected in TgFSHRwt hpg testes. Androgen-regulated and Sertoli cell-specific Rhox5 gene expression was increased in TgFSHR*D567G but not TgFSHRwt hpg testes, providing evidence of elevated LH-independent androgen activity due to mutant FSHR*D567G. Hence, transgenic FSHR overexpression in Sertoli cells revealed that the D567G mutation confers autonomous signaling and steroidogenic activity in vivo as well as promiscuous glycoprotein hormone receptor activation, independently of FSHR overexpression alone.

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Sertoli cell androgen receptor signalling in adulthood is essential for post-meiotic germ cell development

Molecular Reproduction and Development ◽

10.1002/mrd.22506 ◽

2015 ◽

Vol 82 (9) ◽

pp. 626-627 ◽

Cited By ~ 9

Author(s):

Ariane Willems ◽

Cornelia Roesl ◽

Rod T. Mitchell ◽

Laura Milne ◽

Nathan Jeffery ◽

...

Keyword(s):

Androgen Receptor ◽

Germ Cell ◽

Sertoli Cell ◽

Cell Development ◽

Germ Cell Development ◽

Receptor Signalling

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Sertoli and Germ Cell Development in Hypogonadal (hpg) Mice Expressing Transgenic Follicle-Stimulating Hormone Alone or in Combination with Testosterone

Endocrinology ◽

10.1210/en.2002-220710 ◽

2003 ◽

Vol 144 (2) ◽

pp. 509-517 ◽

Cited By ~ 97

Author(s):

Miriam Haywood ◽

Jenny Spaliviero ◽

Mark Jimemez ◽

Nicholas J. C. King ◽

David J. Handelsman ◽

...

Keyword(s):

Germ Cell ◽

Sertoli Cell ◽

Synergistic Effects ◽

Cell Development ◽

Seminiferous Tubules ◽

Germ Cell Development ◽

Cell Numbers ◽

Meiotic Progression ◽

Spermatogonial Proliferation

We recently created a novel transgenic (tg) model to examine the specific gonadal actions of FSH, distinct from LH effects, by expressing tg-FSH in gonadotropin-deficient hypogonadal (hpg) mice. Using this unique in vivo paradigm, we now describe the postnatal cellular development in seminiferous tubules selectively stimulated by tg-FSH alone or combined with testosterone (T). In the αβ.6 line, tg-FSH stimulated the maturation and proliferation (∼2-fold) of Sertoli cells in hpg testes. Total Sertoli cell numbers were also significantly increased (1.5-fold) independently of FSH effects by T treatment alone. Selective FSH activity in αβ.6 hpg testes increased total spermatogonia numbers 3-fold, which established a normal spermatogonia/Sertoli cell ratio. FSH also elevated meiotic spermatocyte numbers 7-fold, notably at pachytene (28-fold), but induced only limited numbers of postmeiotic haploid cells (absent in hpg controls) that arrested during spermatid elongation. In contrast, T treatment alone had little effect on postnatal spermatogonial proliferation but greatly enhanced meiotic progression with total spermatocytes increased 12-fold (pachytene 53-fold) relative to hpg testes, and total spermatid numbers 11-fold higher than tg-FSH hpg testes. Combining tg-FSH and T treatment had no further effect on Sertoli or spermatogonia numbers relative to FSH alone but had marked additive and synergistic effects on meiotic cells, particularly pachytene (107-fold more than hpg), to establish normal meiotic germ cell/Sertoli cell ratios. Furthermore, tg-FSH had a striking synergistic effect with T treatment on total spermatid numbers (19-fold higher than FSH alone), although spermatid to Sertoli cell ratios were not fully restored to normal, indicating elevated Sertoli cell numbers alone are insufficient to establish a maximal postmeiotic germ cell capacity. This unique model has allowed a detailed dissection of FSH in vivo activity alone or with T and provided compelling evidence that FSH effects on spermatogenesis are primarily via Sertoli and spermatogonial proliferation and the stimulation of meiotic and postmeiotic germ cell development in synergy with and dependent on T actions.

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