Nutrient restriction synergizes with retinoic acid to induce mammalian meiotic initiation in vitro

The molecular machinery and chromosome structures carrying out meiosis are frequently conserved from yeast to mammals. However, signals initiating meiosis appear divergent: while nutrient restriction induces meiosis in the yeast system, retinoic acid (RA) and its target Stra8 have been shown to be necessary but not sufficient to induce meiotic initiation in mammalian germ cells. Here, we use primary culture of mouse undifferentiated spermatogonia without the support of gonadal somatic cells to show that nutrient restriction in combination with RA is sufficient to induce Stra8- and Spo11-dependent meiotic gene and chromosome programs that recapitulate the transcriptomic and cytologic features of in vivo meiosis. We demonstrate that neither nutrient restriction nor RA alone exerts these effects. Moreover, we identify a distinctive network of 11 nutrient restriction-upregulated transcription factor genes, which are associated with early meiosis in vivo and whose expression does not require RA. Our study proposes a conserved model, in which nutrient restriction induces meiotic initiation by upregulating key transcription factor genes for the meiotic gene program and provides an in vitro platform for meiotic induction that could facilitate research and haploid gamete production. Retinoic acid is necessary but not sufficient to induce meiosis. Here, the authors use primary mouse undifferentiated spermatogonia culture to show that nutrient restriction, an inducer of yeast meiosis, combined with retinoic acid induces meiotic gene and chromosome programs in mammalian germ cells.

Automated summary

The study demonstrates that nutrient restriction, combined with retinoic acid, is sufficient to induce meiotic gene and chromosome programs in mammalian germ cells. Additionally, a network of 11 nutrient restriction-upregulated transcription factor genes associated with early meiosis is identified, providing insights into the molecular mechanisms of meiotic initiation.