Much is known about the hormonal mechanisms controlling ovarian development. More recently, a major focus of attention in the field has been the identification of regulatory pathways that, operating within the ovarian microenvironment, contribute to the acquisition of ovarian reproductive competence. Within this framework, our laboratory has developed the concept that neurotrophins (NTs) and their Trk tyrosine kinase receptors, long thought to be exclusively required for the development of the nervous system are also involved in the control of ovarian function. Employing gene targeting approaches we identified trkB, the high-affinity receptor for neurotrophin-4/5 (NT-4/5) and brain-derived neurotrophic factor (BDNF), as a signaling molecule required for early follicular growth and oocyte survival. In addition, we showed that nerve growth factor (NGF) contributes independently to the initiation of follicular growth. Other studies indicated that NGF acting via trkA receptors is also important for ovulation, but that despite this physiological role, an inappropriately sustained increase in intraovarian NGF synthesis results in functional alterations leading to the development of follicular cysts. Based on these findings, the present renewal application proposes the following Specific Aims: 1) To define the TrkB receptor isoform (full-length or truncated) required for early follicle growth and oocyte survival, and identify the cells primarily responsive to TrkB signaling. The objectives of this Aim will be achieved using Cre-loxP technology to specifically disrupt the expression of full-length and truncated TrkB isoforms in either oocytes or granulosa cells. 2) To test the hypothesis that NTs signaling via TrkB receptors promote early follicular growth by supporting an oocyte-to granulosa cell Jagged 1-Notch2 communication pathway.
This aim will be achieved with the combined use of cell-specific trkB KOs and cellular/biochemical approaches to define the relationship that exists between TrkB signaling and the Notch2 pathway. 3) To test the hypotheses that while NGF-dependent trkA signaling is required for the normal development of antral follicles and ovulation, an overproduction of NGF compromises the ability of antral follicles to reach a preovulatory stage, and thus establishes conditions leading to the development of polycystic ovaries. To accomplish this Aim we will use transgenic mice that overexpress NGF in a cell specific manner, and mice in which signaling through p75 (the common NT receptor), or trkA (the high-affinity NGF receptor) are conditionally disrupted in ovarian cells. 4) To test the hypothesis that an excess of ovarian NGF creates conditions in the local microenvironment that favor the development of polycystic ovaries in nonhuman primates. To accomplish this Aim we will use a lentiviral delivery system to enhance the production of NGF in the interstitial compartment of the adult nonhuman primate ovary.
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