Role of neurotrophic factors in early ovarian development

Abstract

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.

Figure 1

Folliculogenesis and development of ovarian follicles. Before follicular assembly, oogonia are surrounded by somatic cells of epithelium origin forming “nests” of germ cells and pregranulosa cells. These nests are, in turn, surrounded by mesenchymal cells that proliferate and gradually infiltrate the nests, separating clusters of pregranulosa cells into a more discrete configuration, which allows these cells to surround individual oocytes and form primordial follicles. At the time of follicular assembly, mesenchymal cell proliferation subsides. Primordial follicles consist of a non-growing oocyte with a few associated flattened pregranulosa cells. Primary follicles are those in which granulosa cells have acquired a cuboidal shape and are completely enveloping the oocyte. These follicles can be subdivided into two subtypes: type 3a, which contain a nongrowing oocyte surrounded by no more than 20 granulosa cells, and type 3b in which the oocyte has began to grow and is surrounded by 20–60 granulosa cells. Secondary follicles contain a growing oocyte surrounded by two layers of cuboidal granulosa cells. It is at this stage that granulosa cells begin to acquire responsiveness to FSH.^, FSHR = FSH receptor.

Figure 2

The neurotrophins and their receptors. There are four mammalian neurotrophins (NGF, BDNF, NT-3 ant NT-4/5), three tyrosine kinase receptors (TrkA, TrkB and TrkC) and one pan-NT receptor (p75^NTR). The NTs bind to Trk receptors with high affinity (bold arrows) and to p75^NTR with low affinity (hatched arrows). FL = full-length; T = truncated; Ig = immunoglobulin-like domain; TM = transmembrane domain region; TK = tyrosine kinase domain.

Figure 3

Proposed NT-dependent pathways involved in the control of early follicle development. Current evidence suggest that NGF is produced by both mesenchymal (pre-thecal) and granulosa cells, and acts on TrkA receptors located in both of these cell types to promote the differentiation of primordial follicles into primary follicles, the subsequent growth of primary follicles, and the acquisition of FSH receptors. BDNF and NT-4/5 are produced by granulosa cells (and perhaps, also temporally produced by oocytes), and act on both granulosa cells and the oocyte to promote proliferation of the former, and survival of the latter. They exert these effects by activating FL-TrkB receptors expressed in granulosa cells and T-TrkB receptors expressed in oocytes. Like NGF, BDNF/NT-4/5 also promotes the formation of FSH receptors. Both NT-dependent systems facilitate the biochemical differentiation of growing follicles, prompting them they become responsive to gonadotropins. For details see text. ↑=stimulation; ? = function suspected, but not yet identified.