Nodal signaling regulates the entry into meiosis in fetal germ cells
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Benoit Souquet1, Sophie Tourpin, Sébastien Messiaen
1Commissariat à l'Energie Atomique (CEA)/Direction des Science du Vivant (DSV), Institut de Radiobiologie Cellulaire et Moléculaire (iRCM), Service Cellules Souches et Radiation (SCSR), Laboratoire de Développement des Gonades (LDG), Université Paris Diderot, Sorbonne Paris Cité, France.
Abstract:
The mechanisms regulating the entry into meiosis in mammalian germ cells remain incompletely understood. We investigated the involvement of the TGF-β family members in fetal germ cell meiosis initiation. Nodal, a member of the TGF-β family, and its target genes are precociously expressed in embryonic gonads and show sexual dimorphism in favor of the developing testis. Nodal receptor genes, Acvr2a and Acvr2b, Alk4, and Tdgf1/Cripto, were identified in male germ cells. Nodal itself, Tdgf1, and Lefty1 and Lefty2 are targets of Nodal signaling and were all found specifically expressed in male germ cells. To elucidate the role of this signaling pathway, activin-like kinases that mediate TGF-β/Nodal/activin signaling were inhibited in 11.5 d postconception testis in organotypic culture. Activin-like kinases inhibition disrupted normal male germ cell development and induced germ cell entry into meiosis such as that observed in female germ cells at the equivalent stage. Interestingly Stra8, the gatekeeper of the mitotic/meiotic switch, was induced independently of any change of either Cyp26b1 or Fgf9 expression, the two genes currently identified as testicular meiotic inhibitors. On the other hand, recombinant Nodal significantly dampened Stra8 expression and germ cell meiosis in cultured 11.5 d postconception ovaries. Our results allowed us to propose for the first time an autocrine role of Nodal during the development of germ cells and indicate that members of the TGB-β family may reinforce the male fate and prevent meiosis in embryonic germ cells.
Insights
Transforming Growth Factor-beta (TGF-β) signaling, particularly Nodal, is crucial for mammalian germ cell meiosis. Nodal signaling prevents male germ cells from entering meiosis, reinforcing their male fate.
Area of Science:
- Developmental Biology
- Reproductive Biology
- Cell Signaling
Background:
- Meiosis initiation in mammalian germ cells is a tightly regulated process with incompletely understood mechanisms.
- The Transforming Growth Factor-beta (TGF-β) superfamily, including Nodal, is implicated in embryonic gonad development and exhibits sexual dimorphism.
Purpose of the Study:
- To investigate the role of TGF-β family members, specifically Nodal signaling, in the initiation of meiosis in fetal mammalian germ cells.
- To determine if Nodal signaling influences the male germ cell fate and prevents entry into meiosis.
Main Methods:
- Expression analysis of Nodal and its associated receptor and target genes in embryonic gonads.
- Inhibition of activin-like kinases (ALK) in 11.5 days post-conception (dpc) male gonads cultured in vitro.
- Treatment of 11.5 dpc ovaries with recombinant Nodal in organotypic culture.
Main Results:
- Nodal signaling components and targets were identified in male germ cells, with expression favoring the developing testis.
- Inhibition of ALKs in male germ cells induced precocious entry into meiosis, mimicking female germ cell development.
- Nodal signaling suppressed Stra8 (Stimulated by retinoic acid gene 8) expression and germ cell meiosis in cultured ovaries.
Conclusions:
- Nodal signaling plays an autocrine role in germ cell development, reinforcing male fate and inhibiting meiosis in embryonic male germ cells.
- TGF-β family members are key regulators preventing premature meiosis in male germ cells, distinct from known testicular meiotic inhibitors like Cyp26b1 and Fgf9.
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