scholarly journals Rictor Regulates Spermatogenesis by Controlling Sertoli Cell Cytoskeletal Organization and Cell Polarity in the Mouse Testis

Endocrinology ◽  
2015 ◽  
Vol 156 (11) ◽  
pp. 4244-4256 ◽  
Author(s):  
Heling Dong ◽  
Zhenguo Chen ◽  
Caixia Wang ◽  
Zhi Xiong ◽  
Wanlu Zhao ◽  
...  
Keyword(s):  
Cell Polarity ◽  
Sertoli Cell ◽  
Sertoli Cells ◽  
Cell Function ◽  
Regulatory Protein ◽  
Small Gtpase ◽  
Mutant Mice ◽  
Actin Dynamics ◽  
Testicular Development ◽  
Developmental Defects

Maintenance of cell polarity is essential for Sertoli cell and blood-testis barrier (BTB) function and spermatogenesis; however, the signaling mechanisms that regulate the integrity of the cytoskeleton and polarity of Sertoli cells are not fully understood. Here, we demonstrate that rapamycin-insensitive component of target of rapamycin (TOR) (Rictor), a core component of mechanistic TOR complex 2 (mTORC2), was expressed in the seminiferous epithelium during testicular development, and was down-regulated in a cadmium chloride-induced BTB damage model. We then conditionally deleted the Rictor gene in Sertoli cells and mutant mice exhibited azoospermia and were sterile as early as 3 months old. Further study revealed that Rictor may regulate actin organization via both mTORC2-dependent and mTORC2-independent mechanisms, in which the small GTPase, ras-related C3 botulinum toxin substrate 1, and phosphorylation of the actin filament regulatory protein, Paxillin, are involved, respectively. Loss of Rictor in Sertoli cells perturbed actin dynamics and caused microtubule disarrangement, both of which accumulatively disrupted Sertoli cell polarity and BTB integrity, accompanied by testicular developmental defects, spermiogenic arrest and excessive germ cell loss in mutant mice. Together, these findings establish the importance of Rictor/mTORC2 signaling in Sertoli cell function and spermatogenesis through the maintenance of Sertoli cell cytoskeletal dynamics, BTB integrity, and cell polarity.

scholarly journals Cdc42 activity in Sertoli cells is essential for maintenance of spermatogenesis

2021 ◽  
Author(s):  
Bidur Bhandary ◽  
Anna Heinrich ◽  
Sarah J. Potter ◽  
Nancy Ratner ◽  
Tony DeFalco
Keyword(s):  
Cell Polarity ◽  
Sertoli Cell ◽  
Sertoli Cells ◽  
Rho Gtpase ◽  
Protein Complexes ◽  
Early Adulthood ◽  
Conditional Knockout ◽  
Testicular Development ◽  
Supporting Cells ◽  
Barrier Formation

SUMMARYSertoli cells are highly polarized testicular supporting cells that simultaneously nurture progressively maturing germ cells. Proper localization of polarity protein complexes within Sertoli cells, including those responsible for blood-testis barrier formation, are vital for successful spermatogenesis. However, the mechanisms and developmental timing that underlie the establishment of polarity are poorly understood. To investigate this aspect of testicular function, we conditionally deleted Cdc42, encoding a Rho GTPase involved in regulating cell polarity, specifically in Sertoli cells. Cdc42 deletion disrupted adult Sertoli cell maturation and localization of polarity proteins, but did not affect fetal and early postnatal testicular development, nor the onset of the first wave of spermatogenesis. By early adulthood, however, conditional knockout males exhibited a loss of spermatogenic cells, resulting in a complete lack of sperm. These findings demonstrate that Cdc42 plays an essential role in establishing adult Sertoli cell polarity and, thus, maintaining steady-state spermatogenesis and healthy sperm production.

Role of mammalian Y chromosome in sex determination

1988 ◽  
Vol 322 (1208) ◽  
pp. 63-72 ◽  
Keyword(s):  
Cell Differentiation ◽  
Sex Determination ◽  
Y Chromosome ◽  
Sertoli Cell ◽  
Sertoli Cells ◽  
Sex Reversal ◽  
Testicular Development ◽  
Chimeric Mouse ◽  
Embryonic Gonad

It has long been assumed that the mammalian Y chromosome either encodes, or controls the production of, a diffusible testis-determining molecule, exposure of the embryonic gonad to this molecule being all that is required to divert it along the testicular pathway. My recent finding that Sertoli cells in XX ↔ XY chimeric mouse testes are exclusively XY has led me to propose a new model in which the Y acts cell-autonomously to bring about Sertoli-cell differentiation. I have suggested that all other aspects of foetal testicular development are triggered by the Sertoli cells without further Y-chromosome involvement. This model thus equates mammalian sex determination with Sertoli-cell determination. Examples of natural and experimentally induced sex reversal are discussed in the context of this model.

scholarly journals Exogenous Gonadotrophin Stimulation Induces Partial Maturation of Human Sertoli Cells in a Testicular Xenotransplantation Model for Fertility Preservation

2020 ◽  
Vol 9 (1) ◽  
pp. 266 ◽  
Author(s):  
Marsida Hutka ◽  
Lee B. Smith ◽  
Ellen Goossens ◽  
W. Hamish B. Wallace ◽  
Jan-Bernd Stukenborg ◽  
...  
Keyword(s):  
Sertoli Cell ◽  
Sertoli Cells ◽  
Connexin 43 ◽  
Xenograft Model ◽  
Cell Maturation ◽  
Human Testis ◽  
Testicular Development ◽  
Future Fertility ◽  
And Function ◽  
Testis Tissue

The future fertility of prepubertal boys with cancer may be irreversibly compromised by chemotherapy and/or radiotherapy. Successful spermatogenesis has not been achieved following the xenotransplantation of prepubertal human testis tissue, which is likely due to the failure of somatic cell maturation and function. We used a validated xenograft model to identify the factors required for Leydig and Sertoli cell development and function in immature human testis. Importantly, we compared the maturation status of Sertoli cells in xenografts with that of human testis tissues (n = 9, 1 year-adult). Human fetal testis (n = 6; 14–21 gestational weeks) tissue, which models many aspects of prepubertal testicular development, was transplanted subcutaneously into castrated immunocompromised mice for ~12 months. The mice received exogenous human chorionic gonadotropin (hCG; 20IU, 3×/week). In xenografts exposed continuously to hCG, we demonstrate the maintenance of Leydig cell steroidogenesis, the acquisition of features of Sertoli cell maturation (androgen receptor, lumen development), and the formation of the blood–testis barrier (connexin 43), none of which were present prior to the transplantation or in xenografts in which hCG was withdrawn after 7 months. These studies provide evidence that hCG plays a role in Sertoli cell maturation, which is relevant for future investigations, helping them generate functional gametes from immature testis tissue for clinical application.

scholarly journals Distinct Roles for Rac1 in Sertoli Cell Function during Testicular Development and Spermatogenesis

Cell Reports ◽  
2020 ◽  
Vol 31 (2) ◽  
pp. 107513 ◽  
Author(s):  
Anna Heinrich ◽  
Sarah J. Potter ◽  
Li Guo ◽  
Nancy Ratner ◽  
Tony DeFalco
Keyword(s):  
Sertoli Cell ◽  
Cell Function ◽  
Testicular Development

Adult rat Sertoli cells secrete a factor or factors which modulate Leydig cell function

1987 ◽  
Vol 114 (3) ◽  
pp. 459-467 ◽  
Author(s):  
V. Papadopoulos ◽  
P. Kamtchouing ◽  
M. A. Drosdowsky ◽  
M. T. Hochereau de Reviers ◽  
S. Carreau
Keyword(s):  
Cyclic Amp ◽  
Sertoli Cell ◽  
Leydig Cell ◽  
Sertoli Cells ◽  
Leydig Cells ◽  
Cell Function ◽  
Cell Interaction ◽  
Adult Rats ◽  
Adult Rat ◽  
Stimulating Factor

ABSTRACT Production of testosterone and oestradiol-17β by Leydig cells from adult rats was stimulated by LH or dibutyryl cyclic AMP (10 and 2·5-fold respectively). The addition of spent medium from normal, hemicastrated or γ-irradiated rat seminiferous tubule cultures, as well as from Sertoli cell cultures, to purified Leydig cells further enhanced both basal (44 and 53% for testosterone and oestradiol-17β respectively) and LH-stimulated (56 and 18%) steroid output. Simultaneously, a decrease (20–30%) in intracellular cyclic AMP levels was observed. This stimulating factor (or factors) secreted by the Sertoli cells is different from LHRH, is of proteinic nature and has a molecular weight ranging between 10 000 and 50 000; its synthesis is not controlled by FSH nor by testosterone. This factor(s) involved in rat Leydig cell steroidogenesis, at a step beyond the adenylate cyclase, does not require protein synthesis for testosterone formation whereas it does for oestradiol-17β production. It should be noted that a germ cell–Sertoli cell interaction modulates the synthesis of this factor(s). J. Endocr. (1987) 114, 459–467

Activin is produced by rat Sertoli cells in vitro and can act as an autocrine regulator of Sertoli cell function.

Endocrinology ◽  
1993 ◽  
Vol 132 (3) ◽  
pp. 975-982 ◽  
Author(s):  
J P de Winter ◽  
H M Vanderstichele ◽  
M A Timmerman ◽  
L J Blok ◽  
A P Themmen ◽  
...  
Keyword(s):  
Sertoli Cell ◽  
Sertoli Cells ◽  
Cell Function

scholarly journals Na+/K+-ATPase α1 isoform mediates ouabain-induced expression of cyclin D1 and proliferation of rat Sertoli cells

Reproduction ◽  
2012 ◽  
Vol 144 (6) ◽  
pp. 737-745 ◽  
Author(s):  
Thaís F G Lucas ◽  
Luciana S Amaral ◽  
Catarina S Porto ◽  
Luis E M Quintas
Keyword(s):  
Cyclin D1 ◽  
Sertoli Cell ◽  
Sertoli Cells ◽  
Intracellular Signaling ◽  
Nuclear Translocation ◽  
Binding Protein ◽  
Nuclear Factor Κb ◽  
Camp Response Element Binding ◽  
Testicular Development ◽  
Creb Binding Protein

Novel roles for the interaction of cardiotonic steroids to Na+/K+-ATPase have been established in recent years. The aim of this study was to investigate the intracellular signaling events downstream the action of ouabain on Na+/K+-ATPase in Sertoli cell obtained from immature rats. Treatment of Sertoli cells with ouabain (1 μM) induced a rapid and transient increase in the extracellular signal-regulated kinase (ERK1/2 or MAPK3/1) and phosphatidylinositol 3-kinase (PI3K)/serine–threonine protein kinase (AKT) phosphorylation. Also, ouabain upregulated the expression of cyclin D1 and incorporation of [methyl-3H]thymidine, both of which were dependent on MAPK3/1 but not AKT intracellular cascade, as shown by pretreatment with MEK (MAP2K1/2) inhibitor U0126 and PI3K inhibitor wortmannin respectively. Moreover, the effect of ouabain on these proliferation parameters was completely prevented by phospho-cAMP response element-binding protein (CREB)/CREB-binding protein complex inhibitor KG501 and only partially by nuclear factor κB nuclear translocation inhibitor SN50. Pretreatment with estrogen receptor antagonist ICI 182 780 showed that MAPK3/1 activation by ouabain does not involve this receptor. The Na+/K+-ATPase α1 isoform, but not α4, was detected in Sertoli cells, suggesting that ouabain effects in Sertoli cells are mediated via α1. Taken together, these results show a rapid ouabain action in the Sertoli cells, which in turn can modulate nuclear transcriptional events essential for Sertoli cell proliferation in a critical period of testicular development. Our findings are important to understand the role of ouabain in the testis and its possible implications in male infertility.

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

Animals ◽  
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.

Wnt5a Regulates Junctional Function of Sertoli cells Through PCP-Mediated Effects on mTORC1 and mTORC2

Endocrinology ◽  
2021 ◽  
Author(s):  
Yan Fu ◽  
Yuexin Wei ◽  
Yu Zhou ◽  
Huan Wu ◽  
Yifan Hong ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Sertoli Cell ◽  
Sertoli Cells ◽  
Wnt Signaling Pathway ◽  
Seminiferous Epithelium ◽  
Cell Junctions ◽  
Actin Dynamics ◽  
Actin Binding ◽  
Cell Junction ◽  
Specific Expression

Abstract The blood-testis barrier (BTB) and apical ectoplasmic specialization (ES), which are synchronized through the crosstalk of Sertoli cells and Sertoli-germ cells, are required for spermatogenesis and sperm release. Here, we show that Wnt5a, a noncanonical Wnt signaling pathway ligand, is predominately expressed in both the BTB and apical ES and has a specific expression pattern during the seminiferous epithelium cycle. We employed siRNA to knockdown Wnt5a expression in testis and Sertoli cells and then identified elongated spermatids that lost their polarity, and were embedded in the seminiferous epithelium. Moreover, phagosomes were found near the tubule lumen. These defects were due to BTB and apical ES disruption. We also verified that the expression level and/or location of BTB-associated proteins, actin-binding proteins (ABPs) and F-actin was changed after Wnt5a knockdown in vivo and in vitro. Additionally, we demonstrated that Wnt5a regulated actin dynamics through Ror2-mediated mTORC1 and mTORC2. This study clarified the molecular mechanism of Wnt5a in Sertoli cell junctions through the planar cell polarity (PCP) signaling pathway. Our findings could provide an experimental basis for the clinical diagnosis and treatment of male infertility caused by Sertoli cell junction impairment.

scholarly journals Regulation of the blood-testis barrier by coxsackievirus and adenovirus receptor

2012 ◽  
Vol 303 (8) ◽  
pp. C843-C853 ◽  
Author(s):  
Linlin Su ◽  
Dolores D. Mruk ◽  
C. Yan Cheng
Keyword(s):  
Sertoli Cell ◽  
Sertoli Cells ◽  
Regulatory Protein ◽  
Integral Membrane Protein ◽  
Permeability Barrier ◽  
Structural Protein ◽  
Coxsackievirus And Adenovirus Receptor ◽  
Adenovirus Receptor ◽  
Blood Testis Barrier

The blood-testis barrier (BTB) divides the seminiferous epithelium into the basal and the adluminal compartment. It restricts paracellular diffusion of molecules between Sertoli cells, confers cell polarity, and creates a unique microenvironment in the adluminal compartment for spermatid development. However, it undergoes restructuring during the epithelial cycle so that preleptotene spermatocytes differentiated from type B spermatogonia residing in the basal compartment can traverse the BTB at stage VIII of the cycle, while the immunological barrier is maintained. Herein, coxsackievirus and adenovirus receptor (CAR), a tight junction (TJ) integral membrane protein in the testis and multiple epithelia and endothelia, was found to act as a regulatory protein at the BTB, besides serving as a structural adhesion protein. RNAi-mediated knockdown of CAR in a Sertoli cell epithelium with an established TJ-permeability barrier that mimicked the BTB in vivo resulted in a disruption of the TJ barrier and an increase in endocytosis of the TJ-protein occludin. Furthermore, such an enhancement in occludin endocytosis was accompanied by a downregulation of Thr-phosphorylation in occludin and an increase in the association of endocytosed occludin with early endosome antigen-1. These findings were confirmed by overexpressing CAR in Sertoli cells, which was found to “tighten” the Sertoli cell TJ barrier, promoting BTB function. These findings support the emerging concept that CAR is not only a structural protein, it is involved in conferring the phosphorylation status of other adhesion proteins at the BTB (e.g., occludin) possibly mediated via its structural interactions with nonreceptor protein kinases, thereby modulating endocytic vesicle-mediated protein trafficking.

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