Mechanisms regulating oocyte apoptosis and follicular differentiation during ovarian early follicular growth – EARLYFOLL

The frame of the EARLYFOLL project concerns the mammalian oocyte and its roles on early follicular development and endocrine function. In mammals, female fertility strictly relies on the pool of primordial follicles, which is definitely established around birth. Soon after the formation of this follicular reserve, subsets of primordial follicles continuously enter growth. However, the vast majority of them never reach ovulation and are eliminated by the process of follicular atresia, resulting in the death of the oocyte and companion granulosa cells. So far and contrasting with somatic cells, very few factors playing important roles in DNA integrity have been identified and thus, the mechanisms involved in the protection of the oocyte genome are still poorly understood. Moreover, it has been clearly established that oocyte is crucial to ensure a coordinated development of follicles up to ovulation, notably through regulation of granulosa cell differentiation and endocrine function. However, the fate of the somatic compartment, and thus ovarian function, when oocytes are extensively lost is not fully elucidated.
The purpose of EARLYFOLL is twofold: 1) to gain a better understanding on the molecular mechanisms governing maintenance of genome integrity and apoptosis in oocytes and 2) to elucidate the oocyte roles on early follicular development and endocrine function. EARLYFOLL will take advantage of two original mouse genetic models of oocyte depletion based on oocyte-specific conditional inactivation of Mdm2 and Omcg1, involved in p53 regulation and maintenance of genome integrity, respectively. Mutant females for either gene are sterile and show massive oocyte loss during early follicle growth, a period which is poorly documented. We will investigate the molecular mechanisms underlying this massive loss and in particular the role of p53 family members, notably by transferring our models to p53- and p63-deficient genetic backgrounds. Transcriptome analysis will allow to establish the signature of mutant oocyte committed to death. While both mutant females exhibit an overall similar phenotype, they differ on reproductive physiology. Indeed, Omcg1 mutant females display signs of ovarian steroidogenic function including normal onset of puberty, estrus-type vaginal smear and mating while Mdm2 mutant females do not. We will investigate comparatively the differentiation status of ovarian somatic cells in the absence of oocytes. Global gene expression profiling analysis will allow the identification of new actors in the dialogue between oocyte and somatic cells in early growing follicles. We will also analyse the mechanisms underlying sexual receptivity of Omcg1 mutant females despite the absence of terminal follicular growth and maturation. Because reproductive cyclicity is thougth to be strictly dependent upon appropriate cyclic follicular growth and luteal differentiation, this analysis may lead to a re-evaluation of the current view on the control of estrus cycles in mice.
The EARLYFOLL project brings together a high level of complementary conceptual and methodological expertise, which should enable the integrated analysis of these models, ranging from transcriptome analyses to ovarian and reproductive investigations. It should also provide new data on the dialogue between oocyte and granulosa, which should improve the understanding of female reproductive disorders.