The Molecular Mechanism of Sex Hormones on Sertoli Cell Development and Proliferation

Sustaining and maintaining the intricate process of spermatogenesis is liable upon hormones and growth factors acting through endocrine and paracrine pathways. The Sertoli cells (SCs) are the major somatic cells present in the seminiferous tubules and are considered to be the main regulators of spermatogenesis. As each Sertoli cell supports a specific number of germ cells, thus, the final number of Sertoli cells determines the sperm production capacity. Similarly, sex hormones are also major regulators of spermatogenesis and they can determine the proliferation of Sertoli cells. In the present review, we have critically and comprehensively discussed the role of sex hormones and some other factors that are involved in Sertoli cell proliferation, differentiation and maturation. Furthermore, we have also presented a model of Sertoli cell development based upon the recent advancement in the field of reproduction. Hence, our review article provides a general overview regarding the sex hormonal pathways governing Sertoli cell proliferation and development.

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DDB1 Regulates Sertoli Cell Proliferation and Testis Cord Remodeling by TGFβ Pathway

Genes ◽

10.3390/genes10120974 ◽

2019 ◽

Vol 10 (12) ◽

pp. 974

Author(s):

Wei Zheng ◽

Jabeen Nazish ◽

Fazal Wahab ◽

Ranjha Khan ◽

Xiaohua Jiang ◽

...

Keyword(s):

Cell Proliferation ◽

Sertoli Cell ◽

Sertoli Cells ◽

Transforming Growth Factor ◽

Seminiferous Tubules ◽

Exact Nature ◽

Genetic Ablation ◽

Testis Cord ◽

Tgfβ Pathway

Testis cords are the embryonic precursors of the seminiferous tubules. Development of testis cords is a key event during embryonic testicular morphogenesis and is regulated by multiple signaling molecules produced by Sertoli cells. However, the exact nature and the cascade of molecular events underlying testis cord development remain to be uncovered. In the current study, we explored the role of DNA damage binding protein 1 (DDB1) in Sertoli cells during mouse testis cord development. The genetic ablation of Ddb1 specifically in Sertoli cells resulted in the compromised Sertoli cell proliferation and disruption of testis cord remodeling in neonatal mice. This testicular dysgenesis persisted through adulthood, resulting in smaller testis and low sperm production. Mechanistically, we observed that the DDB1 degradation can stabilize SET domain-containing lysine methyltransferase 8 (SET8), which subsequently decreases the phosphorylation of SMAD2, an essential intracellular component of transforming growth factor beta (TGFβ) signaling. Taken together, our results suggest an essential role of Ddb1 in Sertoli cell proliferation and normal remodeling of testis cords via TGFβ pathway. To our knowledge, this is the first upstream regulators of TGFβ pathway in Sertoli cells, and therefore it furthers our understanding of testis cord development.

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E4 Transcription Factor 1 (E4F1) Regulates Sertoli Cell Proliferation and Fertility in Mice

Animals ◽

10.3390/ani10091691 ◽

2020 ◽

Vol 10 (9) ◽

pp. 1691

Author(s):

Rong-Ge Yan ◽

Qi-Lin Yang ◽

Qi-En Yang

Keyword(s):

Cell Proliferation ◽

Transcription Factor ◽

Sertoli Cell ◽

Sertoli Cells ◽

Cell Function ◽

Conditional Knockout ◽

Seminiferous Tubules ◽

Quiescent State ◽

Testis Size ◽

Cell Fate Decisions

In the mammalian testes, Sertoli cells are the only somatic cells in the seminiferous tubules that provide structural, nutritional and regulatory support for developing spermatogenic cells. Sertoli cells only proliferate during the fetal and neonatal periods and enter a quiescent state after puberty. Functional evidences suggest that the size of Sertoli cell population determines sperm production and fertility. However, factors that direct Sertoli cell proliferation and maturation are not fully understood. Transcription factor E4F1 is a multifunctional protein that serves essential roles in cell fate decisions and because it interacts with pRB, a master regulator of Sertoli cell function, we hypothesized that E4F1 may have a functional role in Sertoli cells. E4f1 mRNA was present in murine testis and immunohistochemical staining confirmed that E4F1 was enriched in mature Sertoli cells. We generated a conditional knockout mouse model using Amh-cre and E4f1flox/flox lines to study E4F1 fucntion in Sertoli cells and the results showed that E4f1 deletion caused a significant reduction in testis size and fertility. Further analyses revealed that meiosis progression and spermiogenesis were normal, however, Sertoli cell proliferation was impaired and germ cell apoptosis was elevated in the testis of E4f1 conditional knockout mice. On the basis of these findings, we concluded that E4F1 was expressed in murine Sertoli cells and served important functions in regulating Sertoli cell proliferation and fertility.

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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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Signal transduction pathways in FSH regulation of rat Sertoli cell proliferation

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00477.2011 ◽

2012 ◽

Vol 302 (8) ◽

pp. E914-E923 ◽

Cited By ~ 49

Author(s):

María F. Riera ◽

Mariana Regueira ◽

María N. Galardo ◽

Eliana H. Pellizzari ◽

Silvina B. Meroni ◽

...

Keyword(s):

Signal Transduction ◽

Cell Proliferation ◽

Sertoli Cell ◽

Sertoli Cells ◽

Kinase Inhibitors ◽

Production Capacity ◽

Signal Transduction Pathways ◽

Mtorc1 Signaling ◽

Mtorc1 Pathway ◽

Cell Mitogen

The final number of Sertoli cells reached during the proliferative periods determines sperm production capacity in adulthood. It is well known that FSH is the major Sertoli cell mitogen; however, little is known about the signal transduction pathways that regulate the proliferation of Sertoli cells. The hypothesis of this investigation was that FSH regulates proliferation through a PI3K/Akt/mTORC1 pathway, and additionally, AMPK-dependent mechanisms counteract FSH proliferative effects. The present study was performed in 8-day-old rat Sertoli cell cultures. The results presented herein show that FSH, in addition to increasing p-Akt, p-mTOR, and p-p70S6K levels, increases p-PRAS40 levels, probably contributing to improving mTORC1 signaling. Furthermore, the decrease in FSH-stimulated p-Akt, p-mTOR, p-p70S6K, and p-PRAS40 levels in the presence of wortmannin emphasizes the participation of PI3K in FSH signaling. Additionally, the inhibition of FSH-stimulated Sertoli cell proliferation by the effect of wortmannin and rapamycin point to the relevance of the PI3K/Akt/mTORC1 signaling pathway in the mitotic activity of FSH. On the other hand, by activating AMPK, several interesting observations were made. Activation of AMPK produced an increase in Raptor phosphorylation, a decrease in p70S6K phosphorylation, and a decrease in FSH-stimulated Sertoli cell proliferation. The decrease in FSH-stimulated cell proliferation was accompanied by an increased expression of the cyclin-dependent kinase inhibitors (CDKIs) p19INK4d, p21Cip1, and p27Kip1. In summary, it is concluded that FSH regulates Sertoli cell proliferation with the participation of a PI3K/Akt/mTORC1 pathway and that AMPK activation may be involved in the detention of proliferation by, at least in part, a decrease in mTORC1 signaling and an increase in CDKI expression.

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Tri-iodothyronine directly affects rat Sertoli cell proliferation and differentiation

Journal of Endocrinology ◽

10.1677/joe.0.1450355 ◽

1995 ◽

Vol 145 (2) ◽

pp. 355-362 ◽

Cited By ~ 40

Author(s):

S Palmero ◽

M Prati ◽

F Bolla ◽

E Fugassa

Keyword(s):

Cell Proliferation ◽

Thyroid Hormone ◽

Sertoli Cell ◽

Sertoli Cells ◽

Aromatase Activity ◽

Functional Maturation ◽

Cell Proliferation And Differentiation ◽

Proliferation And Differentiation ◽

Old Rats

Abstract The addition of physiological concentrations (1 nm) of tri-iodothyronine (T3) to the culture medium of Sertoli cells from prepubertal (8-day-old) rats stimulated both protein synthesis (+55%) and lactate (+50%) production, while it inhibited DNA synthesis (−30/35%) and aromatase activity (−45/50%); insignificant T3-dependent effects were observed in cultured Sertoli cells from midpubertal (28-day-old) rats. These data suggest an age-dependent role for thyroid hormone in promoting and maintaining Sertoli cell differentiation at puberty; moreover, the hormone is involved in the regulation of Sertoli cell proliferation. The present study validates the role of Sertoli cells as a specific target for T3 action at the testis level; it also demonstrates the existence of an early and critical direct influence of thyroid hormone on Sertoli cell proliferation and functional maturation. Journal of Endocrinology (1995) 145, 355–362

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miR-499 promotes immature porcine Sertoli cell growth through the PI3K/AKT pathway by targeting the PTEN gene

Reproduction ◽

10.1530/rep-19-0303 ◽

2020 ◽

Vol 159 (2) ◽

pp. 145-157 ◽

Cited By ~ 3

Author(s):

Hu Gao ◽

Bin Chen ◽

Hui Luo ◽

Bo Weng ◽

Xiangwei Tang ◽

...

Keyword(s):

Cell Proliferation ◽

Cell Growth ◽

Signaling Pathway ◽

Sertoli Cell ◽

Sertoli Cells ◽

Akt Signaling ◽

Akt Pathway ◽

Pten Gene ◽

Seminiferous Tubules ◽

Akt Signaling Pathway

Sertoli cells are indispensable for normal spermatogenesis, and increasing evidence has shown that miRNAs participate in the regulation of Sertoli cell growth. However, the functions and regulatory mechanisms of miRNAs in Sertoli cells of domestic animals have not been fully investigated. In the present study, we mainly investigated the regulatory roles of miR-499 in immature porcine Sertoli cells. The results showed that miR-499 was mainly located in the basement section of seminiferous tubules of prepubertal porcine testicular tissue. Overexpression of miR-499 promoted cell proliferation and inhibited apoptosis, whereas miR-499 inhibition resulted in the opposite effect. The PTEN gene was directly targeted by miR-499, and the expression of mRNA and protein was also negatively regulated by miR-499 in immature porcine Sertoli cells. siRNA-induced PTEN knockdown resulted in a similar effect as an overexpression of miR-499 and abolished the effects of miR-499 inhibition on immature porcine Sertoli cells. Moreover, both miR-499 overexpression and the PTEN knockdown activated the PI3K/AKT signaling pathway, whereas inhibition of the PI3K/AKT signaling pathway caused immature porcine Sertoli cell apoptosis and inhibited cell proliferation. Overall, miR-499 promotes proliferation and inhibits apoptosis in immature porcine Sertoli cells through the PI3K/AKT pathway by targeting the PTEN gene. This study provides novel insights into the effects of miR-499 in spermatogenesis through the regulation of immature Sertoli cell proliferation and apoptosis.

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BRG1 Is Dispensable for Sertoli Cell Development and Functions in Mice

International Journal of Molecular Sciences ◽

10.3390/ijms21124358 ◽

2020 ◽

Vol 21 (12) ◽

pp. 4358

Author(s):

Shuai Wang ◽

Pengxiang Wang ◽

Dongli Liang ◽

Yuan Wang

Keyword(s):

Sertoli Cell ◽

Germ Cells ◽

Sertoli Cells ◽

Cell Development ◽

Conditional Knockout ◽

Mouse Strains ◽

Seminiferous Tubules ◽

Supporting Cells ◽

Knockout Mouse Model ◽

Conditional Knockout Mouse

Sertoli cells are somatic supporting cells in spermatogenic niche and play critical roles in germ cell development, but it is yet to be understood how epigenetic modifiers regulate Sertoli cell development and contribution to spermatogenesis. BRG1 (Brahma related gene 1) is a catalytic subunit of the mammalian SWI/SNF chromatin remodeling complex and participates in transcriptional regulation. The present study aimed to define the functions of BRG1 in mouse Sertoli cells during mouse spermatogenesis. We found that BRG1 protein was localized in the nuclei of both Sertoli cells and germ cells in seminiferous tubules. We further examined the requirement of BRG1 in Sertoli cell development using a Brg1 conditional knockout mouse model and two Amh-Cre mouse strains to specifically delete Brg1 gene from Sertoli cells. We found that the Amh-Cre mice from Jackson Laboratory had inefficient recombinase activities in Sertoli cells, while the other Amh-Cre strain from the European Mouse Mutant Archive achieved complete Brg1 deletion in Sertoli cells. Nevertheless, the conditional knockout of Brg1 from Sertoli cells by neither of Amh-Cre strains led to any detectable abnormalities in the development of either Sertoli cells or germ cells, suggesting that BRG1-SWI/SNF complex is dispensable to the functions of Sertoli cells in spermatogenesis.

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127. An α6β1-integrin/focal adhesion kinase complex may regulate spermiation and spermiation failure

Reproduction Fertility and Development ◽

10.1071/srb04abs127 ◽

2004 ◽

Vol 16 (9) ◽

pp. 127

Author(s):

A. J. Beardsley ◽

D. M. Robertson ◽

L. O'Donnell

Keyword(s):

Sertoli Cell ◽

Sertoli Cells ◽

Seminiferous Tubules ◽

Β1 Integrin ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Cell Plasma ◽

Hormone Sensitive ◽

Adhesion Complex

Spermiation is the final step of spermatogenesis (sperm production) where mature spermatids are released from the somatic Sertoli cells. Spermiation is hormone sensitive; testosterone (T) and FSH withdrawal causes a disruption to the disengagement of spermatids, which are instead retained by Sertoli cells. The mechanisms involved with spermatid release and retention are not understood. We showed previously that an unknown adhesion junction containing β1-integrin persisted on retained spermatids suggesting that a defect in this adhesion complex at disengagement may underlie spermiation failure. The aim of this study is to identify the α-integrin dimerised with β1-integrin and investigate the role of phosphorylated FAK, a kinase that is involved with integrin-mediated cell adhesion, during spermiation and spermiation failure. Four adult Sprague-Dawley rats received T and oestradiol implants and FSH antibody for 7A days to suppress testicular T and FSH and induce spermiation failure. Using immunohistochemistry, α6-integrin (but not α4-integrin) and FAK-Tyr397 were localised on the Sertoli cell plasma membrane adjacent to mature spermatids. This localisation was observed until the point of spermatid release and remained on the Sertoli cell that surrounded retained spermatids after hormone suppression. A similar localisation has been previously observed with β1-integrin, suggesting that all three form a complex at the site of disengagement. To look at the function of FAK-Tyr397, comparative Western blot analysis is currently being undertaken on seminiferous tubules specific for spermiation from control and treated animals. Preliminary studies suggest that FAK-Tyr397 remains phosphorylated during spermiation failure, suggesting that FAK dephosphorylation may be important for the function of spermatid-associated adhesion complexes, as has been demonstrated in other adhesion systems. In conclusion, α6β1-integrin/FAK-containing adhesion complexes are associated with spermatids during spermiation, and the function of such complexes are likely to be perturbed during spermiation failure.

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Role of Akt and mammalian target of rapamycin signalling in insulin-like growth factor 1-mediated cell proliferation in porcine Sertoli cells

Reproduction Fertility and Development ◽

10.1071/rd19460 ◽

2020 ◽

Vol 32 (10) ◽

pp. 929

Author(s):

Chinju Johnson ◽

John Kastelic ◽

Jacob Thundathil

Keyword(s):

Cell Proliferation ◽

Growth Factor ◽

Sertoli Cell ◽

Sertoli Cells ◽

Cholesterol Biosynthesis ◽

Critical Role ◽

Mammalian Target Of Rapamycin ◽

Target Of Rapamycin ◽

Insulin Like Growth Factor

The critical role of insulin-like growth factor (IGF) 1 in promoting Sertoli cell proliferation invivo and invitro has been established, but its downstream signalling mechanisms remain unknown. In addition to mitogenic effects, a role for IGF1 in mediating cholesterol biosynthesis within testes has been implied. The aims of this study were to investigate the roles of: (1) phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (mTOR) signalling in IGF1-mediated Sertoli cell proliferation; and (2) IGF1 in mediating cholesterol biosynthesis in Sertoli cells. Primary cultures of Sertoli cells were prepared from 1-week-old porcine testes. On Day 3 of culture, Sertoli cells were treated with 300ng mL−1 IGF1, alone or in combination with inhibitors of IGF1 receptor (2μM picropodophyllotoxin), Akt (1μM wortmannin) or mTOR (200nM rapamycin). Cells were cultured for 30min and phosphorylation levels of Akt, mTOR and p70 ribosomal protein S6 kinase (p70S6K) were determined by immunoblotting. Cell proliferation and quantitative polymerase chain reaction assays were conducted using cells cultured for 24h. IGF1 increased phosphorylation of Akt, mTOR and p70S6K and cell proliferation, and these effects were inhibited by inhibitors of IGF1R, Akt and mTOR. Furthermore, IGF1 upregulated the expression of cholesterol biosynthetic genes (3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS1) and cytochrome P450, family 5, subfamily A, polypeptide 1 (CYP5A1)), but not sterol regulatory element-binding transcription factor 1 (SREBF1). Increased phosphorylation of p70S6K, a major downstream target of mTOR, and upregulated expression of genes involved in cholesterol biosynthesis are indicative of the key role played by IGF1 in regulating the synthesis of cholesterol, the precursor for steroid hormones.

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