A ROLE FOR TRKA NERVE GROWTH-FACTOR RECEPTORS IN MAMMALIAN OVULATION

Several members of the neurotrophin (NT) family, including nerve growt h factor (NGF), NT-3, and NT-4/5, are expressed in the mammalian ovary . ks their respective receptor tyrosine kinases are also found in the gland, the possibility exists that NTs act directly on the gonads to e xert effects unrelated to their support of the ovarian innervation. We now report that trkA, the NGF receptor tyrosine kinase, is involved i n the acute activational process that leads to the first ovulation. Th e trkA gene becomes transiently expressed in periovulatory follicles a t the time of the first preovulatory surge of gonadotropins at puberty ; the increase in trkA messenger RNA (mRNA) content is dramatic(> 100- fold), but transient (similar to 9 h). No such changes in trkB or trkC mRNA were observed; the abundance of these mRNAs, which encode the re ceptor tyrosine kinases for NT-4/5 and brain-derived neurotrophic fact or, and NT-3, respectively, remained at very low levels throughout pub erty. In vivo and in vitro experiments demonstrated that the activatio n of trkA gene expression is brought about by the proestrous discharge of LH. The increase in trkA mRNA levels is mainly localized to cells of the follicular wall and interstitial tissue of the ovary. NGF mRNA abundance also increases at proestrus, with peak values detected about 5 h before ovulation; as in the case of trkA mRNA, NGF mRNA was found in thecal-interstitial cells. Both trkA and NGF protein, detected by immunohistochemistry, were localized to this same ovarian compartment. Interleukin-1 beta (IL-1 beta), a putative mediator of LH action, enh ances both trkA and NGF gene expression in ovarian cells, an effect pr evented by IL-1ra, a natural IL-1 beta receptor antagonist. IL-1 beta also stimulates PGE(2) release, and this effect was inhibited by both NGF antibodies and a trh receptor blocker; NGF antibodies administered in vivo attenuated the increase in ovarian PGE(2) synthesis that ante dates ovulation. Immunoneutralization of NGF action or pharmacological blockade of trh tyrosine kinase activity targeted to one ovary result ed in the ipsilateral inhibition of ovulation. The remarkably narrow t ime frame of trkA gene activation at the completion of follicular grow th suggests that NGF acting as a neuroendocrinotrophic factor in a dev elopmentally restricted manner contributes to the acute cytodifferenti ation process that leads to the first ovulation in mammals.