VEGF and SEMA3A selectively control different stages of GnRH neuron development independently of blood vessels

Gonadotropin-releasing hormone (GnRH) neurons are neuroendocrine cells that are born outside the brain and migrate along olfactory and vomeronasal axons to reach the hypothalamus, where they regulate sexual reproduction. By combining genetic mouse models with cell and molecular approaches, we show here that the development of the GnRH neuronal system relies on the synergistic action of two distinct neuropilin-mediated signalling pathways. Thus, the vascular endothelial growth factor isoform VEGF164 signals through NRP1 to promote the survival of migrating GnRH neurons via PI3K and ERK1/2 activation; unexpectedly, we found that this pathway operates independently of KDR, the VEGF receptor previously implicated in neuronal survival. Concomitantly, SEMA3A signals through NRP1 and, unconventionally, NRP2, to pattern the axonal scaffold that guides the migrating GnRH neurons. The combined loss of VEGF164 and SEMA3A therefore precludes the establishment of the GnRH neuronal system, demonstrating that VEGF164 and SEMA3A cooperate to coordinate neuronal migration with survival.