VEGF and semaphorins modulate the migration of GnRH-secreting neurons: link with the blood vessels?

Aim: Gonadotropin-releasing hormone (GnRH) neurons originate in the olfactory placode and during development (E11-E18 in mouse) migrate along olfactory nerves to reach the hypothalamus. We have recently described that neuropilins NRP1 and NRP2, co-receptors for two distinct classes of molecules (the class 3 semaphorins, SEMAs, and the vascular endothelial growth factor A, VEGFA), are expressed by GnRH neurons. In this study, a possible correlation between blood vessels formation and GnRH-system has been investigated. Methods: E12-12.5 mice were processed for immunocytochemistry and RT-PCR analysis. GN11 neurons were cultured in DMEM/10%FBS and used for RT-PCR and microchemotaxis assay in Boyden’s chamber. Results: Using a specific marker for neoforming blood vessels (isolectin B4), we found that at E12.5, concomitantly with the start of migration of GnRH neurons, the mouse olfactory placode is densely surrounded by small blood vessels. Accordingly, we demonstrated by RT-PCR the expression of SEMA3A, SEMA3F and VEGF in E12 mouse nasal tissue. We also found that immortalised GnRH neurons (GN11 cells) express NRP1 and NRP2, as well as FLT1 and that recombinant SEMA3A and 3F inhibited the their chemomigration in vitro. However, VEGFA exerted an opposite effect, suggesting that the migration of GnRH neurons may be the results of a balance between negative (SEMAs) and positive (VEGFA) cues. Conclusions: Taken together, these preliminary data raise the possibility that GnRH neuron migration is influenced by SEMAs and VEGF signalling, suggesting that a ‘cross-talk’ between the vascular and GnRH-neuron systems can occur to control their development. (granted by PRIN 2005051740)