Hypoxia induces the dormant state in oocytes through expression of Foxo3

In mammals, most immature oocytes remain dormant in the primordial follicles in order to ensure the longevity of female reproductive life. A precise understanding of mechanisms underlying the dormancy is important for reproductive biology and medicine. In this study, by comparing mouse oogenesis in vivo and in vitro, the latter of which bypasses the primordial follicle stage, we defined the gene　expression profile representing the dormant state of oocytes. Overexpression of constitutively active FOXO3 partially reproduced the dormant state in vitro. Based on further gene expression analysis, we found that a hypoxic condition efficiently induced the dormant state in vitro. The effect of hypoxia was severely diminished by disruption of the Foxo3 gene and inhibition of hypoxia-inducible factors. Our findings provide insights into the importance of environmental conditions and their effectors for establishing the dormant state. Transcriptomes of oocytes isolated from in vivo ovaries at various stages or in vitro-reconstituted ovaries at various days of culture were determined by RNA-seq analysis. Transcriptomes of in vitro D21 oocytes derived from WT ESCs and Foxo3dNES Tg ESCs under a normoxic or hypoxic condition were also determined. Biologically triplicated (rep1-3) or duplicated (rep1-2) samples were analyzed.