Abstract
Recent studies have demonstrated that neurotrophins (NTs) and their NTRK tyrosine kinase receptors, thought to be exclusively required for the development of the nervous system, are also involved in controlling ovarian development. Here, we show that primordial follicle formation is decreased in the absence of nerve growth factor (NGF) or its receptor NTRK1, and in the absence of NTRK2, the receptor for neurotrophin-4 (NTF4) and brain-derived neurotrophic factor (BDNF). This deficiency is not due to premature oocyte loss, because the ovaries of Ntrk1(-/-) and Ntrk2(-/-) mice do not show an increased rate of oocyte death antedating the initiation of folliculogenesis. Moreover, exposure of NGF-deficient ovaries to NGF rescues the defect in follicular assembly, if NTRK1 receptors are present, suggesting that the absence of NTs causes a delay, and not an irretrievable loss, of follicle formation. Both the number of secondary follicles and FSH receptor (FSHR) expression are diminished in Ntrk1- and Ntrk2-null ovaries, but not in ovaries lacking the common NT receptor NGFR. Transient exposure of wild-type ovaries to NTF4 increases Fshr gene expression and enhances the ability of the ovary to respond to FSH with formation of cyclin D2, a cell cycle protein mediating the proliferative actions of FSH in the ovary. These results indicate that both NTRK1 and NTRK2 receptors are necessary for the timely assembly of primordial follicles and for sustaining early follicular development. They also suggest that a mechanism by which NTRK2 receptors facilitate subsequent follicle development is by inducing the formation of functional FSHR.