Critical gaps remain in our understanding of the molecular mechanisms that regulate the maintenance of ovarian primordial follicles. Primordial follicle activation, the first step of an elaborate process (follicular maturation) that culminates in egg release (ovulation), is the metered process by which primordial follicles are selected from the reserve pool into the growing follicle pool. We have shown that 1) the forkhead transcription factor Foxo3 is a molecular switch that functions within oocytes to actively regulate this process throughout life; 2) the ?on/off? state of Foxo3 depends on its nuclear vs. cytoplasmic localization and phosphorylation status; and 3) the state of this switch is controlled by the PI3K/Pten-Akt signalling pathway. Here we propose to expand upon this previous work to establish the identify of the putative receptor tyrosine kinase (RTK) that regulates this process and thus the utilization of the primordial follicle supply during life. Based on preliminary data and efforts, we propose to rigorously test via genetic means the hypothesis that Kit serves as the key RTK regulating this fundamental reproductive process. These studies will depend upon two novel and complementary gain-of-function and loss-of-function alleles of Kit we developed specifically for this purpose. These studies will provide a unique opportunity to fill a critical knowledge gap relating to primary ovarian insufficiency and create new genetic model systems for the study of primordial follicle activation and early menopause syndromes.
An improved understanding of the pathways and upstream effectors that regulate primordial follicle activation in the ovary, combined with new genetic model systems for their study, will lead to insights into the biological and genetic basis of female infertility and primary ovarian insufficiency (also known as premature ovarian failure). This will in turn create significant opportunities to develop predictive genetic tests for hereditary forms of female infertility, and may some day lead to the development of improved contraceptives that preserve primordial follicles.
| Saatcioglu, Hatice Duygu; Cuevas, Ileana; Castrillon, Diego H (2016) Control of Oocyte Reawakening by Kit. PLoS Genet 12:e1006215 |
