Nodal signaling regulates the entry into meiosis in fetal germ cells.

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.