Endocrine Abstracts

Reproduction in mammals is centrally regulated by neuroendocrine neurons scattered in the hypothalamus and secreting the decapeptide GnRH (gonadotropin releasing hormone). During development, GnRH-secreting neurons originate in the olfactory placode – at least in rodents – and migrate along olfactory nerves (the vomeronasal and the terminalis) to gain access to the forebrain and reach their final destinations in the hypothalamus. Defects in the migration of these neurons in humans result in infertility. The mechanisms underlying the establishment of the migration route and the movement of GnRH neurons are not very well understood and are thought to involve different classes of molecules. Candidates comprise semaphorins and their receptors (neuropilins) because of their high levels of expression in the developing olfactory system, which is intimately related with the development of the GnRH neurons. Moreover, reproductive problems and defects in the fasciculation of the vomeronasal nerves have been reported in the mutant mice for Neuropilin-2 (Npn-2), one of the class III semaphorins receptors, leading to investigate the role of these molecules in the migration of GnRH neurons. Analysis of newborn Npn-2^−/− mice showed a significant reduction in number of GnRH neurons within the brain but an abnormal presence of such neurons stacked in the nasal regions. Expression studies performed on RNA derived from GFP-GnRH FACS-sorted cells showed presence of Npn-1, 2 and their ligands (Sema3A, 3F), suggesting the importance of these molecules in this system. In vitro experiments using immortalized GnRH neurons (GN11) showed that semaphorins 3A and 3F inhibit their migration, whereas VEGF, another Npn-2 ligand, reverted this effect, suggesting the possibility that in vivo the migration of the GnRH neurons might be influenced by a balance between positive (VEGFs) and negative (semaphorins) cues, acting through common receptors (neuropilins). These findings provide new insights into the molecular mechanisms of the migration of GnRH neurons and propose new candidate genes, likely involved in the pathogenesis of hypogonadotropic hypogonadisms.