Neurotrophic and cell-cell dependent control of early follicular development.

Neurotrophins (NTs) and their receptors play an essential role in the differentiation and survival of defined neuronal populations of the central and peripheral nervous systems. Their actions, however, do not appear to be limited to the nervous system, as both NTs and their receptors have been found in non neuronal cells, including cells of the endocrine system. At least four of the five known neurotrophins, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4), and their receptors (p75 NTR, trkA, trkB and trkC) are present in the developing ovary. Using mice carrying null mutations of the genes encoding neurotrophins (NGF, NT-4, BDNF) or the receptor that mediates the actions of NT-4 and BDNF (trkB), we have obtained initial results consistent with the notion that neurotrophins are required for the growth of primordial follicles. NGF-deficient mice show a decreased formation of both primary and secondary preantral follicles. Null mutation of the NT-4 gene failed to affect either folliculogenesis or follicular development. However, formation of primary and secondary follicles was compromised in mice carrying a null mutation of both the NT-4 and BDNF genes, suggesting compensation of function by BDNF in NT-4 knockouts. Support for this concept is provided by the similar deficiency in follicular growth observed in animals carrying a null mutation of the gene encoding trkB, the receptors mediating NT-4 and BDNF actions. Initial experiments, using differential display, to isolate genes that may be involved in the process of folliculogenesis and/or early follicular development, resulted in the isolation of a recently identified cell adhesion molecule and a novel transcription factor originally shown to induce cell transformation. It thus appears that formation and development of mammalian follicles requires the concerted action of genes originally thought to be only involved in cell differentiation/survival of neuronal cells, and genes that may control the growth, differentiation, and cell-cell interactions of somatic and germ cells in the ovary.