Essential to sexual reproduction is the generation of haploid gametes from diploid germ cells through meiosis. Germ cells initiate meiosis during fetal life in females, but at puberty in males. This temporal difference is believed to depend solely on the fetal gonadal somatic environment. The signalling molecule retinoic acid triggers meiosis in both sexes, as it stimulates expression of pre-meiotic transcription factors STRA8 and MEIOSIN, which together drive extensive transcriptional change. Despite this progress, the molecular mechanisms underlying mitosis-to-meiosis transition remain poorly understood.
Working with primordial germ cell-like cells (PGCLCs) in vitro, researchers recently showed that retinoic acid alone is unable to direct the oogenic fate, and that BMP is also required in their system1, with ZGLP1 being the critical downstream target essential to ensure progression through oogenesis2. To establish whether BMP signalling is also required in vivo, we used a mouse model that is deficient for BMP receptor 1A (BMPR1A) specifically in the germ cells, and showed that BMPR1A-mediated signalling is indeed necessary for normal female mouse fetal germ cell meiosis. Germ cell-specific loss of BMP signalling does not affect the initiation of Stra8 expression, but it does slow meiotic progression and compromises mitotic exit. Interestingly, disruption of BMPR1A-mediated BMP signalling abolishes the expression of Cdx2 – a homeobox gene crucial for the first cell fate decision in early embryos. CDX2 is transiently expressed in female fetal germ cells just prior to meiotic entry, and slightly earlier than the pre-meiotic factors STRA8 and MEIOSIN.
Our study has demonstrated an in vivo role for BMP signalling in fetal germ cell meiosis and identified CDX2 as a potential effector. Understanding how germ cells lose pluripotency and commit to sex-specific fate is relevant to stem cell biology, and our findings will hopefully inform ongoing attempts to generate safe effective gametes, in vitro.