VEGF IS INVOLVED IN THE MIGRATION OF GnRH-SECRETING NEURONS: INTERACTION WITH SEMAPHORINS SIGNALING ON NPN2 RECEPTOR

The molecular cues regulating the migratory process of GnRH neurons from the olfactory placode to the brain are not yet well clarified, but gradients of chemotropic and chemorepellent factors secreted by their targets are likely to play a key role in the mechanisms leading to migratory process. Defects in the migration of these neurons in humans result in infertility. A large part of the migratory pathway is in the nasal tissue, therefore mesenchyme-derived factors may play an important role in such a process. Recent data show that migration of GnRH neurons appears to be concomitant to an intense vasculogenesis in the nasal mesenchyme suggesting that it may provide signals also to direct neuronal migration. Among the factors that may affect angiogenesis, vascular endothelial growth factors (VEGF) play a relevant role; moreover, reproductive problems have been reported in the mutant mice for Neuropilin-2 (Npn-2), one of the class III semaphorins receptors also involved in the VEGF signaling, prompting us 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 showed presence of Npn1 and 2 in GFP-GnRH FACS-sorted neurons. In addition, we found that immortalized GnRH neurons (GN11) express Npn1 and 2 as well as the Flk-1/KDR type of VEGF receptor; the exposure to a VEGF gradient induces a significant dose-related chemomigration of GN11 cells that can be reverted by the exposure to semaphorins 3A and 3F also ligands of Npn2. These data indicate that VEGF cues may affect the migration of the GnRH neurons through Flk1 specific receptors as well as by interaction with semaphorins signals on Npn2 receptor. These findings provide new insights into the molecular mechanisms of the migration of GnRH neurons; the mild phenotype of Npn-2-/- mice propose Npn2 as a new candidate genes likely involved in the pathogenesis of hypogonadotropic hypogonadisms. (Grants: PRIN2005 # 2005051740)