VEGF189 binds NRP1 and is sufficient for VEGF/NRP1-dependent neuronal patterning in the developing brain.
Bottom Line: Alternative splicing of the Vegfa gene gives rise to three major isoforms termed VEGF121, VEGF165 and VEGF189.VEGF165 binds the transmembrane protein neuropilin 1 (NRP1) and promotes the migration, survival and axon guidance of subsets of neurons, whereas VEGF121 cannot activate NRP1-dependent neuronal responses.By contrast, the role of VEGF189 in NRP1-mediated signalling pathways has not yet been examined.
Affiliation: UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK.Show MeSH
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Mentions: As a third model to study VEGF188 in neurodevelopment, we investigated GnRH neuron survival. GnRH neurons are born in the nasal placode and travel along nasal axons to reach the forebrain (Fig. 4A; Cariboni et al., 2007). We have previously shown that Vegfa120/120 mice have significantly fewer migrating GnRH neurons and demonstrated that VEGF164 signals through NRP1 to promote the survival of GN11 cells, which recapitulate many features of migratory GnRH neurons (Cariboni et al., 2011). We therefore examined whether VEGF188 promotes GN11 survival, similar to VEGF164. Whereas 72 h of serum withdrawal caused the death of over half of the GN11 cells, the inclusion of serum, VEGF164 or VEGF188 for the last 12 h of culture significantly reduced cell death, and VEGF188 was as effective as VEGF164 in preventing cell death; by contrast, and as expected, VEGF120 did not promote survival (Fig. 4B; percentage of propidium iodide-positive cells, mean±s.e.m.: control, 44±3%; serum, 2±1%; VEGF120, 37±3; VEGF164, 11±2%; VEGF188, 11±2%). These observations suggest that VEGF188, similar to VEGF164, can promote GnRH neuron survival. The ineffectiveness of VEGF120 agreed with the previously observed NRP1-dependent neuroprotection of GN11 cells and the fact that Vegfa120/120 mice have fewer GnRH neurons (Cariboni et al., 2011). Also in agreement with the in vitro findings, the GnRH neuron number was normal in Vegfa188/188 mice that express VEGF188 but lack VEGF164 (Fig. 4C,D). Moreover, replacing one Vegfa120 allele in Vegfa120/120 mutants with the Vegfa188 allele was sufficient to prevent their GnRH neuron survival defect (Fig. 4C,D). Together, these data show that VEGF188 is sufficient to promote NRP1-dependent neuronal survival.Fig. 4.
Affiliation: UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK.