Signaling Pathways Regulating Ovarian Follicle Formation

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A fundamental determinant of a successful pregnancy outcome is the quality of the oocyte that will be fertilized to form the zygote. The health of the oocyte is, in turn, a direct reflection of the follicle environment and the interactions between germ cells and somatic support cells that nurture the oocyte to ovulation. The studies proposed invesfigate the formation of the ovarian follicle, and are applicable to understanding how the health of the oocyte is maintained and how aberrations in follicle assembly might contribute to infertility. This research investigates roles for key developmental signaling pathways in the establishment of the inifial follicle pool. During ovarian organogenesis, germ cell syncytia, or 'nests' undergo breakdown to form the primordial follicles that will support reproducfion in the adult. Agents that disrupt breakdown of germ cell nests and follicle formation have adverse impacts on reproductive health. Our studies and those of others idenfify Notch, activin and estrogen signaling as being important for germ cell nest breakdown and normal follicle formation in the ovary, and furthermore reveal that mis-regulation of these pathways results in the formation of aberrant follicles. We hypothesize that each of these signals play important but distinct roles in follicle formation, with 1) Notch regulafing granulosa-germ cell interactions and promoting granulosa cell identity, 2) acfivin sfimulafing granulosa cell proliferafion, and 3) estrogen inhibifing nest breakdown in part through its cross-regulation of Notch and activin signaling. We propose to investigate these novel roles, as well as to examine the integrafion of these signaling pathways in the neonatal mouse ovary. Aim 1 will ufilize a novel ex vivo ovary culture system as well as conditional knockout mice to investigate mechanisms by which Notch signaling regulates somatic pre-granulosa cell function and facilitates germ cell nest breakdown and follicle formafion. Aim 2 will utilize the ovarian culture system, as well as gene expression profiling approaches, to establish mechanisms and target genes by which activin signaling regulates ovarian cell death or proliferation and enhances follicle formation. Aim 3 will examine cross-regulation between these signaling pathways to determine if the repressive effects of estrogen on germ cell nest breakdown are mediated by interacfions with the Notch and activin signaling pathways. Studies invesfigafing the signaling pathways that regulate germ cell and somatic cell functions and interactions in the developing ovary, processes which impact the formation of follicles capable of maturing and ovulafing a healthy oocyte, will certainly enhance our ability to identify, understand and eventually treat diseases or disorders that adversely affect follicle health and pregnancy outcome. We anticipate that the basic research studies described in this proposal will contribute to that important effort and will eventually advance human reproductive health.