Neurotrophic and cell-cell dependent control of early follicular development

Neurotrophins (NTs) and their receptors play an essential role in the diffe rentiation and survival of defined neuronal populations of the central and peripheral nervous systems. Their actions, however, do not appear to be lim ited 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 f our of the five known neurotrophins, including nerve growth factor (NGF), b rain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotr ophin-4, (NT-4), and their receptors (p75 NTR: trkA, trkB and trkC) are pre sent in the developing ovary. Using mice carrying null mutations of the gen es encoding neurotrophins (NGF, NT-4, BDNF) or the receptor that mediates t he actions of NT-4 and BDNF (trkB), we have obtained initial results consis tent with the notion that neurotrophins are required for the growth of prim ordial folljcles. NGF-deficient mice show a decreased formation of both pri mary and secondary preantral follicles. Null mutation of the NT-4 gene fail ed to affect either folliculogenesis or follicular development. However, fo rmation of primary and secondary follicles was compromised in mice carrying a null mutation of both the NT-4 and BDNF genes, suggesting compensation o f 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 an d 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 t o induce cell transformation. It thus appears that formation and developmen t of mammalian follicles requires the concerted action of genes originally thought to be only involved in cell differentiation/survival of neuronal ce lls, and genes that may control the growth, differentiation, and cell-cell interactions of somatic and germ cells in the ovary. (C) 2000 Elsevier Scie nce Ireland Ltd. All rights reserved.