Role of Neurotrophic Factors in Early Ovarian Development

Much is known about the endocrine hormonal mechanisms controlling ovarian development. More recently, attention has focused on identifying regulatory pathways that, operating within the ovarian microenvironment, contribute to the acquisition of ovarian reproductive competence. Within this framework, the concept has developed 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 maturation. The ovary of several species, including rodents, sheep, cows, nonhuman primates, and humans, produce NTs and express both the high-affinity receptors and the common p75(NTR) receptor required for signaling. Studies in humans and rodents have shown that this expression is initiated during fetal life, before the formation of primordial follicles. Gene targeting approaches have identified TrkB, the high-affinity receptor for neurotrophin-4/5 and brain-derived neurotrophic factor, as a signaling module required for follicular assembly, early follicular growth, and oocyte survival. A similar approach has shown that nerve growth factor contributes independently to the growth of primordial follicles into gonadotropin-responsive structures. Altogether, these observations indicate that NTs are important contributors to the gonadotropin-independent process underlying the formation and initiation of ovarian follicular growth.