The Role and Branching Dynamics of Sympathetic Nerves in Ovarian Folliculogenesis

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PROJECT SUMMARY/ABSTRACT Although infertility affects 10% of women between the ages of 15 and 44 in the United States, fundamental gaps in knowledge surround ovary development. Ovarian folliculogenesis, defined as the production of mature and competent oocytes for ovulation, is a highly organized process that is critical for fertility. In mammals, the ‘ovarian reserve’ is comprised of single immature oocytes surrounded by a layer of somatic cells. This unit, known as a primordial follicle, remains non-growing until it activates and transitions through morphologically distinct stages of growth to support oocyte maturation. Follicle maturation occurs twice in mammalian life during separate waves of growth: first, around birth and second, at the onset of puberty. Distinct from the 2nd wave, which is initiated by release of gonadotropin hormone at puberty, the mechanisms underlying how 1st wave follicles are chosen to mature during this gonadotropin-independent wave remain elusive. As evidence indicates that sympathetic innervation may be involved in 1st wave follicle maturation, I propose to define the role and branching dynamics of sympathetic nerves (SNs) in the 1st wave of folliculogenesis. The overall hypothesis is that SNs innervate growing follicles via both autocrine and paracrine signaling and function to prime 1st wave follicles for gonadotropin-control. Elucidating how SNs influence female reproductive maturation and the mechanisms critical for establishing SN networks during the 1st wave of folliculogenesis will glean critical insights into the basic biology of this essential process and provide a platform for understanding ovarian disease pathogenesis. Leveraging innovative mouse genetics, whole organ clearing, 3D imaging, and quantitative analysis approaches, this proposal will: first, generate a 3D spatiotemporal map of SNs during 1st wave follicle maturation in the neonatal ovary; second, investigate the function of SNs in the 1st wave of follicle maturation; and third, interrogate the role of non-canonical Wnt-Ror1/2 signaling in the branching dynamics of SNs during the 1st wave of folliculogenesis. Sponsor Dr. Laird and co-sponsor Dr. Knox have complementary expertise in the fields of reproductive biology, genetic mouse models, 3D whole organ imaging and analysis, organogenesis, and peripheral nerve biology. Their collective expertise alongside the F31 Fellowship support assures the training and mentorship necessary to complete the proposed research.