Role of VEGF and blood vessels during GnRH-neurons development

Gonadotropin-releasing hormone (GnRH) neurons, a small number of neuroendocrine cells scattered in the hypothalamus, play an important role in reproduction. During development, GnRH neurons are born in the olfactory placode and migrate along olfactory nerves in the nasal compartment to gain access into the forebrain and reach the hypothalamus. In humans, defects in their migration result in infertility. The mechanisms involved in the migration of GnRH neurons are under investigation. We have recently described that classical guidance molecules, such neuropilins (NRPs), are expressed by GnRH neurons, and established the importance of NRP2 in their migration in vivo. Using immortalised GnRH-neurons, we found that two distinct NRP ligands regulate their migratory response: the class 3 semaphorins and vascular endothelial growth factor A (VEGF). VEGF is a major regulator of vasculogenesis, interacting with receptor tyrosine kinases (Flt-1/Flk-1) on endothelial cells. Recent evidence indicates that VEGF has additional non vascular-functions. In particular, VEGF can act directly on neurons to produce different effects such survival, axonal elongation and migration. In this study, the interactions between blood vessels and GnRH-system have been tested. Using RT-PCR and enzymatic stainings of VEGF-LacZ reporter mice, we found that VEGF is significantly expressed in the nasal region during development. We also visualised the presence of a network of blood vessels along the migratory path of GnRH neurons. Moreover, isolated mouse embryonic GnRH neurons express specific transcripts for VEGF and Flt-1. Functionally, we found that VEGF exerts pleiotropic effects on immortalised GnRH-neurons, acting on survival, chemomigration and axonal elongation. Taken together, these novel data raise the possibility that GnRH neuronal migration and development are modulated by VEGF signalling, suggesting the existence of a cross-talk between the vascular and GnRH-neuron system