Essential to sexual reproduction is the generation of haploid gametes from diploid germ cells through meiosis – a germline-exclusive, specialised reductive form of cell division. In females, germ cells lose pluripotency and initiate meiosis during fetal life, but male germ cells only enter meiosis at puberty. This temporal difference in meiotic onset is believed to be dependent solely on the fetal gonadal somatic environment, not the chromosome constitution of the germ cells (XX vs XY). We have known for some years that the extrinsic signalling molecule retinoic acid (RA) is indispensable for meiosis in both sexes; RA 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 remains poorly understood.
Working with primordial germ cell-like cells (PGCLC) in vitro, Miyauchi et al. recently showed that RA alone is unable to direct the oogenic fate, and that BMP is also required in their system1, with ZGLP1 being the critical downstream target of BMP signalling2. They concluded that STRA8/MEIOSIN initiate meiosis while ZGLP1 is important to ensure progression through oogenesis. To establish whether BMP is also required in vivo, we used an ex vivo gonad culture model and in vivo mouse model, deficient for BMP receptor 1A (BMPR1A) specifically in the germ cells, and showed that BMP signalling through BMPR1A is required for timely transition to meiosis in female mouse fetal germ cells. Germ cell-specific loss of BMP signalling delays meiotic onset and progression without affecting the initiation of Stra8 expression. Based on previous in vitro work2, we further confirmed that Zglp1 is a target of BMP signalling in germ cells, in vivo. Interestingly, disruption of BMPR1A-mediated BMP signalling ex vivo and in vivo abolishes the expression of Cdx2 – a homeobox gene crucial for cell fate specification in various contexts during early embryonic development. CDX2 is transiently expressed in female fetal germ cells just prior to meiotic entry, earlier than STRA8 and MEIOSIN.
Our study has demonstrated an in vivo role for BMP signalling in fetal germ cell meiosis and identified a potential BMP effector, CDX2. We are now testing whether CDX2 plays a crucial role(s) in this important developmental process. Understanding how germ cells lose pluripotency and commit to sex-specific fate is relevant to stem cell biology in general, and we hope our findings will inform ongoing attempts to generate safe effective gametes, in vitro.