Nutrient restriction, inducer of yeast meiosis, induces meiotic initiation in mammals

ABSTRACT From yeasts to mammals, the molecular machinery and chromosome structures carrying out meiosis are frequently conserved. However, the signal to initiate meiosis appears divergent: while nutrient restriction induces meiosis in the yeast system, retinoic acid (RA), a chordate morphogen, is necessary but not sufficient to induce meiotic initiation in mammalian germ cells via its target, Stra8 . Here, using cultured mouse male germline stem cells without the support of gonadal somatic cells, we show that nutrient restriction in combination with RA robustly induces Spo11 -dependent meiotic DNA double strand breaks (DSBs) and Stra8 -dependent meiotic gene programs recapitulating those of early meiosis in vivo . Moreover, a distinct network of 11 nutrient restriction-upregulated transcription factor genes was identified, whose expression does not require RA and is associated with early meiosis in vivo . Thus, our study proposes a conserved model, in which nutrient restriction induces meiotic initiation by upregulating transcriptional factors for meiotic gene programs, and provides an in vitro platform to derive haploid gametes in culture. One Sentence Summary nutrient restriction synergizes with retinoic acid to induce mammalian meiotic initiation