Control of Oocyte Reawakening by Kit
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In mammals, oocyte reawakening is a fundamental biological process controlling follicle maturation, female fertility, the onset of the menopause, and thus, overall aging. We demonstrate through complementary genetic experiments that Kit is the upstream receptor regulating reawakening within oocytes. Although many factors have been proposed as candidates, the data have remained contradictory, and definitive genetic evidence in support of any factor has been lacking. We engineered two novel Kit alleles in mice, one a dominant gain-of-function point mutation active in the germline, the other a floxed allele for conditional inactivation. These alleles permitted us to conduct elegant genetic experiments whereby Kit was activated or inactivated in primordial oocytes. The results were complementary and striking. Oocyte-specific Kit activation resulted in a syndrome of female sterility due to global and premature reawakening leading to ovarian failure. In contrast, Kit inactivation also led to female sterility, albeit via a contrasting and opposite phenotype: a complete failure of primordial follicles to reawaken. Additional studies demonstrated that Foxo3 was the mediator of both phenotypes, linking our findings to prior discoveries. These complementary genetic experiments thus definitively incriminate Kit as the upstream receptor regulating reawakening. We believe our study will be of interest to general scientific and lay audiences as well as geneticists, given the importance of oocyte maintenance in the menopause, overall female aging, and reproduction.