Abstract
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.
Highlights
The molecular machinery and chromosome structures carrying out meiosis are frequently conserved from yeast to mammals
Our recent work in stimulated by retinoic acid gene 8 (Stra8)-deficient mice reveals that an autophagy-inducing factor is engaged on meiosis-initiating germ cells[24]
The molecular machinery and chromosomal dynamics underlying this process is often conserved from yeasts to mammals, the signal to induce meiosis appears different: nutrient restriction induces meiotic initiation in the yeast system, whereas retinoic acid (RA), a chordate morphogen, and its signaling have been the primary focus in mammals
Summary
The molecular machinery and chromosome structures carrying out meiosis are frequently conserved from yeast to mammals. Hormad genes encode meiosis-specific chromosome factors (Hop[1] in yeasts and Hormad1/2 in mammals) that are critical for synapsis and DSB formation and repair[7,8] Despite these evolutionary conservations in meiotic genes and structures, the overarching signal to initiate meiosis appears divergent. Culture has been successfully developed in several mammalian species[18,19,20], a direct means to induce meiotic initiation in these cells in vitro remains as an unmet challenge[21] As an example, this was be achieved by reintroducing cultured male GSCs back into the seminiferous tubules on the organ culture system[22], suggesting that gonadal somatic cell support is indispensable for this process. This prevents faithful recapitulation of meiosis and reconstitution of spermatogenesis in vitro under a defined culture condition, which possesses enormous value in investigating the delicate process of meiosis as well as in vitro production of haploid gametes that assist animal and, human reproduction[23]
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