scholarly journals Testicular Somatic Cells, not Gonocytes, Are the Major Source of Functional Activin A during Testis Morphogenesis

Endocrinology ◽  
2011 ◽  
Vol 152 (11) ◽  
pp. 4358-4367 ◽  
Author(s):  
Denise R. Archambeault ◽  
Jessica Tomaszewski ◽  
Andrew J. Childs ◽  
Richard A. Anderson ◽  
Humphrey Hung-Chang Yao
Keyword(s):  
Cell Proliferation ◽  
Sertoli Cell ◽  
Somatic Cells ◽  
Activin A ◽  
Protein Product ◽  
Conditional Knockout ◽  
Seminiferous Tubules ◽  
Testis Size ◽  
Testis Development ◽  
Testis Cord

Proper development of the seminiferous tubules (or testis cords in embryos) is critical for male fertility. Sertoli cells, somatic components of the seminiferous tubules, serve as nurse cells to the male germline, and thus their numbers decide the quantity of sperm output in adulthood. We previously identified activin A, the protein product of the activin βA (Inhba) gene, as a key regulator of murine Sertoli cell proliferation and testis cord expansion during embryogenesis. Although our genetic studies implicated fetal Leydig cells as the primary producers of testicular activin A, gonocytes are another potential source. To investigate the relative contribution of gonocyte-derived activin A to testis morphogenesis, we compared testis development in the Inhba global knockout mouse, which lacks activin A production in all cells (including the gonocytes), and a steroidogenic factor 1 (Sf1)-specific conditional knockout model in which activin A expression in testicular somatic cells is disrupted but gonocyte expression of activin A remains intact. Surprisingly, testis development was comparable in these two models of activin A insufficiency, with similar reductions in Sertoli cell proliferation and minor differences in testis histology. Thus, our findings suggest activin A from male gonocytes is insufficient to promote Sertoli cell proliferation and testis cord expansion in the absence of somatic cell-derived activin A. Evaluation of adult male mice with fetal disruption of activin A revealed reduced testis size, lowered sperm production, altered testicular histology, and elevated plasma FSH levels, defects reminiscent of human cases of androgen-sufficient idiopathic oligozoospermia.

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.

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

Genes ◽  
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.

Development of Testis Cords and the Formation of Efferent Ducts in Xenopus laevis: Differences and Similarities with Other Vertebrates

2021 ◽  
pp. 1-14
Author(s):  
Yuanyuan Li ◽  
Jinbo Li ◽  
Man Cai ◽  
Zhanfen Qin
Keyword(s):  
Cell Proliferation ◽  
Xenopus Laevis ◽  
Germ Cells ◽  
Sertoli Cells ◽  
Testis Development ◽  
Larval Stages ◽  
Efferent Ducts ◽  
Steroidogenic Cells ◽  
Testis Cord ◽  
Anterior Posterior

The knowledge of testis development in amphibians relative to amniotes remains limited. Here, we used Xenopus laevis to investigate the process of testis cord development. Morphological observations revealed the presence of segmental gonomeres consisting of medullary knots in male gonads at stages 52–53, with no distinct gonomeres in female gonads. Further observations showed that cell proliferation occurs at specific sites along the anterior-posterior axis of the future testis at stage 50, which contributes to the formation of medullary knots. At stage 53, adjacent gonomeres become close to each other, resulting in fusion; then (pre-)Sertoli cells aggregate and form primitive testis cords, which ultimately become testis cords when germ cells are present inside. The process of testis cord formation in X. laevis appears to be more complex than in amniotes. Strikingly, steroidogenic cells appear earlier than (pre-)Sertoli cells in differentiating testes of X. laevis, which differs from earlier differentiation of (pre-)Sertoli cells in amniotes. Importantly, we found that the mesonephros is connected to the testis gonomere at a specific site at early larval stages and that these connections become efferent ducts after metamorphosis, which challenges the previous concept that the mesonephric side and the gonadal side initially develop in isolation and then connect to each other in amphibians and amniotes.

scholarly journals The Type 3 Deiodinase Is a Critical Determinant of Appropriate Thyroid Hormone Action in the Developing Testis

Endocrinology ◽  
2016 ◽  
Vol 157 (3) ◽  
pp. 1276-1288 ◽  
Author(s):  
M. Elena Martinez ◽  
Aldona Karaczyn ◽  
J. Patrizia Stohn ◽  
William T. Donnelly ◽  
Walburga Croteau ◽  
...  
Keyword(s):  
Gene Expression ◽  
Thyroid Hormone ◽  
Critical Factor ◽  
Monocarboxylate Transporter ◽  
Seminiferous Tubules ◽  
Testis Size ◽  
Critical Determinant ◽  
Testis Development ◽  
Neonatal Testis ◽  
Type 3

Abstract Timely and appropriate levels of thyroid hormone (TH) signaling are necessary to ensure normal developmental outcomes in many tissues. Studies using pharmacological models of altered TH status have revealed an influence of these hormones on testis development and size, but little is known about the role of endogenous determinants of TH action in the developing male gonads. Using a genetic approach, we demonstrate that the type 3 deiodinase (D3), which inactivates TH and protects developing tissues from undue TH action, is a key factor. D3 is highly expressed in the developing testis, and D3-deficient (D3KO) mice exhibit thyrotoxicosis and cell proliferation arrest in the neonatal testis, resulting in an approximately 75% reduction in testis size. This is accompanied by larger seminiferous tubules, impaired spermatogenesis, and a hormonal profile indicative of primary hypogonadism. A deficiency in the TH receptor-α fully normalizes testis size and adult testis gene expression in D3KO mice, indicating that the effects of D3 deficiency are mediated through this type of receptor. Similarly, genetic deficiencies in the D2 or in the monocarboxylate transporter 8 partially rescue the abnormalities in testis size and gonadal axis gene expression featured in the D3KO mice. Our study highlights the testis as an important tissue in which determinants of TH action coordinately converge to ensure normal development and identifies D3 as a critical factor in testis development and in testicular protection from thyrotoxicosis.

Npat ‐dependent programmed Sertoli cell proliferation is indispensable for testis cord development and germ cell mitotic arrest

2019 ◽  
Vol 33 (8) ◽  
pp. 9075-9086 ◽  
Author(s):  
Xiaohua Jiang ◽  
Shi Yin ◽  
Suixing Fan ◽  
Jianqiang Bao ◽  
Yuying Jiao ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Germ Cell ◽  
Sertoli Cell ◽  
Mitotic Arrest ◽  
Testis Cord

scholarly journals Activin A Decreases glucagon and arx Gene Expression in α-Cell Lines

2007 ◽  
Vol 21 (1) ◽  
pp. 259-273 ◽  
Author(s):  
Aline Mamin ◽  
Jacques Philippe
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Cell Lines ◽  
Human Islets ◽  
Activin A ◽  
Protein Product ◽  
Control Element ◽  
Transcriptional Level ◽  
Dependent Manner ◽  
Β Cells

Abstract Activin A is a potent growth and differentiation factor involved in development, differentiation, and physiological functions of the endocrine pancreas; it increases insulin and pax4 gene expression in β-cells and can induce transdifferentiation of the exocrine acinar cell line AR42J into insulin-producing cells. We show here that Activin A decreases glucagon gene expression in the α-cell lines InR1G9 and αTC1 in a dose- and time-dependent manner and that the effect is blocked by Follistatin. This effect is also observed in adult human islets. Glucagon gene expression is inhibited at the transcriptional level by the Smad signaling pathway through the G3 DNA control element. Furthermore, Activin A decreases cell proliferation of InR1G9 and αTC1 cells as well as cyclin D2 and arx gene expression, whose protein product Arx has been shown to be critical for α-cell differentiation. Overexpression of Arx in Activin A-treated InR1G9 cells does not prevent the decrease in glucagon gene expression but corrects the inhibition of cell proliferation, indicating that Arx mediates the Activin A effects on the cell cycle. We conclude that Activin A has opposite effects on α-cells compared with β-cells, a finding that may have relevance during pancreatic endocrine lineage specification and physiological function of the adult islets.

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