Expression of neurotrophins and their receptors in the mammalian ovary is developmentally regulated: Changes at the time of folliculogenesis

An emerging body of evidence suggests that neurotrophins not only promote neuronal survival and differentiation, but can also target nonneuronal cells for their actions. Neurotrophins initiate their biological effects by binding to cell membrane tyrosine kinase receptors of the trk protooncogene family. In addition, all neurotrophins recognize with similar affinity a different receptor molecule known as p75 nerve growth factor receptor (p75 NGFR) or low affinity NGFR, which appears to interact with the trk receptors to potentiate their response to neurotrophins. The mature mammalian ovary has been shown to synthesize several neurotrophins, including nerve growth factor (NGF), neurotrophin 3 (NT-3), and neurotrophin 4/5 (NT-4/5). The ovary also expresses some of the neurotrophin receptors, including p75 NGFR, trkB [the receptor for NT-4/5 and brain-derived neurotropic factor (BDNF)], and trkA (the NGF receptor). The present experiments were undertaken to determine whether neurotrophins and their receptors are expressed at the time of definitive ovarian histogenesis, and whether any of them exhibit a developmental pattern of expression related to the completion of folliculogenesis. Immunohistochemical identification of p75 NGFR in rat embryonic ovaries revealed that the receptor is predominantly expressed in mesenchymal cells. By gestational day 18, these cells have formed pockets that enclose presumptive pregranulosa cells and groups of oocytes into ovigerous cords. Immediately after birth, the ovigerous cords are subdivided, resulting in the abrupt formation of primordial follicles between 24-48 h after birth. Consistent with these observations, the p75 NGFR messenger RNA (mRNA) content increased after birth and remained elevated at the time of follicular assembly. The NGF and trkA genes showed a different pattern of expression, as the ovarian content of both NGF and trkA mRNA decreased at the time of folliculogenesis. In contrast to the drop in NGF and trkA mRNA expression, NT-4 mRNA levels increased at the time of follicular assembly, coinciding with the abrupt appearance of trkB mRNA. In situ hybridization showed that the increase in NT-4 mRNA expression occurred in a subpopulation of oocytes between 24-48 h after birth, and that the trkB gene became predominantly expressed at this time in epithelial pregranulosa cells. Substantial, but unchanging, levels of NT-3 mRNA and the mRNA encoding trkC, the preferred NT-3 receptor, were detected throughout the perinatal period examined. Very low and invariable levels of BDNF were also detected. The mirroring patterns of NGF/trkA and NT-4/trkB gene expression highlighting the period of follicular assembly, the lack of detectable changes in the mRNAs encoding the NT-3/trkC ligand-receptor system, and the negligible levels of BDNF mRNA (which encodes the other trkB ligand) detected at this time suggest that NGF and NT-4 are the neurotrophins most likely to play a role during perinatal ovarian development. The possibility exists that NGF and NT-4 play different, but complementary, roles in ovarian histogenesis, with the former facilitating predifferentiation events, and the latter influencing processes such as the organization of germ and somatic cells into follicular structures and/or the initiation of follicular growth.