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.