We previously demonstrated that Nodal/Activin signalling is active in male germ cells during fetal development. Its role is to drive germ cell towards the male fate, by driving expression of male fate genes such as Nanos2and Dnmt3l. Others have proposed that Nodal signalling also acts to protect male germ cells from entering meiosis. Nodal is a TGFbmolecule and signals using the Type I and II TGFbreceptors; generally the presence of the co-receptor Cripto is also required. Criptoexpression is driven by FGF9 during a short period of time (11.5dpc to 13.5dpc) in male germ cells and we have linked this to maintenance of the pluripotent state.
Given the importance of FGF signalling and Nanos2expression in spermatogonial stem cell (SSC) maintenance in the postnatal testis, we explored whether Cripto was also involved in SSC biology. We find that Criptois highly expressed in mouse gonocytes in the juvenile testis while its expression is restricted to a few spermatogonia in the adult. Criptoover-expression in germ cells after birth leads to infertility and a gradual loss of germ cells from P7 onwards. Young adult mutant testis have only a few undifferentiated spermatogonia that are lost over time. The first wave of differentiation is impaired, with germ cells maintaining expression of PLzfwhile lacking Stra8expression, showing that mutant cells do not enter meiosis. Preliminary analysis of Criptoconditional-KO in germ cells suggests that loss of Cripto does not affect spermatogenesis per se but, rather, affects the number of SSCs. Overall, we propose a role for Cripto in driving self-renewal (as opposed as differentiation) in undifferentiated spermatogonia, possibly by modulating sensitivity to retinoic acid prior to the start of the first wave of spermatogenesis – when SSCs are specified.