Transforming growth factor beta (TGFβ1, TGFβ2 and TGFβ3) null-mutant phenotypes in embryonic gonadal development

Memon, Mushtaq A.; Anway, Matthew D.; Covert, Trevor R.; Uzumcu, Mehmet; Skinner, Michael K.

doi:10.1016/j.mce.2008.08.017

Cited by 69 publications

(56 citation statements)

References 50 publications

(58 reference statements)

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“…Gene knockout studies have demonstrated that FGF9 signalling is essential for testis development, but deletion of activin or TGFβ genes have relatively mild effects (Shull et al 1992, Colvin et al 2001, Schmahl et al 2004, Kim et al 2006, 2007, Bagheri-Fam et al 2008, Memon et al 2008, Archambeault & Yao 2010, Moreno et al 2010, Mendis et al 2011. Consistent with this, this study demonstrated that ex vivo exposure of XX gonads to FGF9 promoted changes in XX gonad characteristic of the developing testis, including supporting cell proliferation, repression of ovarian genes and promotion of male germ line development.…”

Section: Growth Factors Fgf9 Activin and Tgfβ Promote Testicular Chasupporting

confidence: 68%

“…Blocking activin/TGFβ signalling at E11.5 or E12.5 significantly reduces Sertoli cell proliferation and disrupts testis cord formation , indicating that activin-TGFβ signalling promotes testis formation in the critical sex-determining window at E11.5. However, testes develop in mice that lack Inhba, Inhbb or individual Tgfβ genes, demonstrating that they are individually dispensable for male sex determination (Shull et al 1992, Memon et al 2008, Archambeault & Yao 2010, Moreno et al 2010, Mendis et al 2011, although the possibility that these factors compensate for one another's function in testis development has not been addressed.…”

Section: Introductionmentioning

confidence: 99%

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FGF9, activin and TGFβ promote testicular characteristics in an XX gonad organ culture model

et al. 2016

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Testis development is dependent on the key sex-determining factors SRY and SOX9, which activate the essential ligand FGF9. Although FGF9 plays a central role in testis development, it is unable to induce testis formation on its own. However, other growth factors, including activins and TGFβs, also present testis during testis formation. In this study, we investigated the potential of FGF9 combined with activin and TGFβ to induce testis development in cultured XX gonads. Our data demonstrated differing individual and combined abilities of FGF9, activin and TGFβ to promote supporting cell proliferation, Sertoli cell development and male germ line differentiation in cultured XX gonads. FGF9 promoted proliferation of supporting cells in XX foetal gonads at rates similar to those observed in vivo during testis cord formation in XY gonads but was insufficient to initiate testis development. However, when FGF9, activin and TGFβ were combined, aspects of testicular development were induced, including the expression of Sox9, morphological reorganisation of the gonad and deposition of laminin around germ cells. Enhancing β-catenin activity diminished the testis-promoting activities of the combined growth factors. The male promoting activity of FGF9 and the combined growth factors directly or indirectly extended to the germ line, in which a mixed phenotype was observed. FGF9 and the combined growth factors promoted male germ line development, including mitotic arrest, but expression of pluripotency genes was maintained, rather than being repressed. Together, our data provide evidence that combined signalling by FGF9, activin and TGFβ can induce testicular characteristics in XX gonads.Reproduction (2016) 152 529-543

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Section: Growth Factors Fgf9 Activin and Tgfβ Promote Testicular Chasupporting

confidence: 68%

Section: Introductionmentioning

confidence: 99%

FGF9, activin and TGFβ promote testicular characteristics in an XX gonad organ culture model

et al. 2016

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“…As the central component of canonical TGF-β superfamily signaling, deletion of SMAD4 should eliminate canonical TGF-β signaling to the Sertoli cells (24). Although numerous TGF-β superfamily ligands, including AMH, TGF-β1, TGF-β2, TGF-β3, and activin B are produced in embryonic testes, testis cord dysgenesis has not been reported in murine models lacking these genes (19,(25)(26)(27). We therefore hypothesized that any changes in testis cord development in the Sertoli-specific Smad4 conditional knockout model (Amh cre/+ ;Smad4 fl/− or Smad4 cKO) would result from the inability of Sertoli cells to respond to fetal Leydig cell-derived activin A.…”

Section: Sertoli Cell-specific Ablation Of Smad4 Recapitulates Testismentioning

confidence: 99%

Activin A, a product of fetal Leydig cells, is a unique paracrine regulator of Sertoli cell proliferation and fetal testis cord expansion

Archambeault

Yao

2010

Proc. Natl. Acad. Sci. U.S.A.

125

112

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Formation of tubular structures relies upon complex interactions between adjacent epithelium and mesenchyme. In the embryonic testes, dramatic compartmentalization leads to the formation of testis cords (epithelium) and the surrounding interstitium (mesenchyme). Sertoli cells, the epithelial cell type within testis cords, produce signaling molecules to orchestrate testis cord formation. The interstitial fetal Leydig cells, however, are thought only to masculinize the embryo and are not known to be involved in testis cord morphogenesis. Contrary to this notion, we have identified activin A, a member of the TGF-β protein superfamily, as a product of the murine fetal Leydig cells that acts directly upon Sertoli cells to promote their proliferation during late embryogenesis. Genetic disruption of activin βA, the gene encoding activin A, specifically in fetal Leydig cells resulted in a failure of fetal testis cord elongation and expansion due to decreased Sertoli cell proliferation. Conditional inactivation of Smad4 , the central component of TGF-β signaling, in Sertoli cells led to testis cord dysgenesis and proliferative defects similar to those of Leydig cell-specific activin βA knockout testes. These results indicate that activin A is the major TGF-β protein that acts directly on Sertoli cells. Testicular dysgenesis in activin βA and Smad4 conditional knockout embryos persists into adulthood, leading to low sperm production and abnormal testicular histology. Our findings challenge the paradigm that fetal testis development is solely under the control of Sertoli cells, by uncovering an active and essential role of fetal Leydig cells during testis cord morphogenesis.

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“…Furthermore, a TGF-bRII knockout experiment likewise verified that TGF-b plays an important role in germ cell proliferation and apoptosis. Stéphanie et al (2010), Memon et al (2008), and others have also shown that TGF-b1 and TGF-b3 are both expressed in mouse embryonic testes, and Mai et al (2010) noted that TGF-b is necessary for testis development following a functional defect analysis in mice.…”

Section: Bmp4 Promotes Escs To Differentiate Into Male Germ Cellsmentioning

confidence: 99%

Effects of the Transforming Growth Factor Beta Signaling Pathway on the Differentiation of Chicken Embryonic Stem Cells into Male Germ Cells

Zhang

Wang

Zuo

et al. 2016

Cellular Reprogramming

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The objectives of the present study were to screen for key gene and signaling pathways involved in the production of male germ cells in poultry and to investigate the effects of the transforming growth factor beta (TGF-b) signaling pathway on the differentiation of chicken embryonic stem cells (ESCs) into male germ cells. The ESCs, primordial germ cells, and spermatogonial stem cells (SSCs) were sorted using flow cytometry for RNA sequencing (RNA-seq) technology. Male chicken ESCs were induced using 40 ng/mL of bone morphogenetic protein 4 (BMP4). The effects of the TGF-b signaling pathway on the production of chicken SSCs were confirmed by morphology, quantitative real-time polymerase chain reaction, and immunocytochemistry. One hundred seventy-three key genes relevant to development, differentiation, and metabolism and 20 signaling pathways involved in cell reproduction, differentiation, and signal transduction were identified by RNA-seq. The germ cells formed agglomerates and increased in number 14 days after induction by BMP4. During the induction process, the ESCs, Nanog, and Sox2 marker gene expression levels decreased, whereas expression of the germ cell-specific genes Stra8, Dazl, integrin-a6, and c-kit increased. The results indicated that the TGF-b signaling pathway participated in the differentiation of chicken ESCs into male germ cells.

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Transforming growth factor beta (TGFβ1, TGFβ2 and TGFβ3) null-mutant phenotypes in embryonic gonadal development

Cited by 69 publications

References 50 publications

FGF9, activin and TGFβ promote testicular characteristics in an XX gonad organ culture model

FGF9, activin and TGFβ promote testicular characteristics in an XX gonad organ culture model

Activin A, a product of fetal Leydig cells, is a unique paracrine regulator of Sertoli cell proliferation and fetal testis cord expansion

Effects of the Transforming Growth Factor Beta Signaling Pathway on the Differentiation of Chicken Embryonic Stem Cells into Male Germ Cells

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