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VEGF189 binds NRP1 and is sufficient for VEGF/NRP1-dependent neuronal patterning in the developing brain.

Tillo M, Erskine L, Cariboni A, Fantin A, Joyce A, Denti L, Ruhrberg C - Development (2014)

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.

View Article: PubMed Central - PubMed

Affiliation: UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK.

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VEGF188 is sufficient to promote GnRH neuron survival. (A) GnRH neuron migration (blue dots). The neurons are born in the nasal placodes that give rise to the olfactory and vomeronasal epithelia (OE, VNO) and migrate along olfactory and vomeronasal axons (purple, Olf/VN) through the nasal compartment (NC) to reach the forebrain (FB). (B) Serum-starved GN11 cells were treated with DMEM or DMEM-containing serum, VEGF120, VEGF164 or VEGF188; cell death was visualised by propidium iodide staining (red); Hoechst staining (blue) identified the total number of cells. Scale bar: 25 µm. (C) Sagittal sections of E14.5 mouse heads of the indicated genotypes, immunolabelled for GnRH. Arrows indicate migrating neurons; arrowheads indicate blood vessels; open triangles indicate the absence of migrating neurons; dotted lines indicate the FB boundary. OB, olfactory bulb. Scale bar: 100 µm. (D) GnRH neuron number in E14.5 heads of the indicated genotypes (mean±s.e.m.): control, 1246±46, n=6; Vegfa120/120, 854±21, n=5; Vegfa188/188, 1335±63, n=3; Vegfa120/188, 1314±58, n=3; t-test; ***P<0.001 compared with control.
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DEV115998F4: VEGF188 is sufficient to promote GnRH neuron survival. (A) GnRH neuron migration (blue dots). The neurons are born in the nasal placodes that give rise to the olfactory and vomeronasal epithelia (OE, VNO) and migrate along olfactory and vomeronasal axons (purple, Olf/VN) through the nasal compartment (NC) to reach the forebrain (FB). (B) Serum-starved GN11 cells were treated with DMEM or DMEM-containing serum, VEGF120, VEGF164 or VEGF188; cell death was visualised by propidium iodide staining (red); Hoechst staining (blue) identified the total number of cells. Scale bar: 25 µm. (C) Sagittal sections of E14.5 mouse heads of the indicated genotypes, immunolabelled for GnRH. Arrows indicate migrating neurons; arrowheads indicate blood vessels; open triangles indicate the absence of migrating neurons; dotted lines indicate the FB boundary. OB, olfactory bulb. Scale bar: 100 µm. (D) GnRH neuron number in E14.5 heads of the indicated genotypes (mean±s.e.m.): control, 1246±46, n=6; Vegfa120/120, 854±21, n=5; Vegfa188/188, 1335±63, n=3; Vegfa120/188, 1314±58, n=3; t-test; ***P<0.001 compared with control.

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.


VEGF189 binds NRP1 and is sufficient for VEGF/NRP1-dependent neuronal patterning in the developing brain.

Tillo M, Erskine L, Cariboni A, Fantin A, Joyce A, Denti L, Ruhrberg C - Development (2014)

VEGF188 is sufficient to promote GnRH neuron survival. (A) GnRH neuron migration (blue dots). The neurons are born in the nasal placodes that give rise to the olfactory and vomeronasal epithelia (OE, VNO) and migrate along olfactory and vomeronasal axons (purple, Olf/VN) through the nasal compartment (NC) to reach the forebrain (FB). (B) Serum-starved GN11 cells were treated with DMEM or DMEM-containing serum, VEGF120, VEGF164 or VEGF188; cell death was visualised by propidium iodide staining (red); Hoechst staining (blue) identified the total number of cells. Scale bar: 25 µm. (C) Sagittal sections of E14.5 mouse heads of the indicated genotypes, immunolabelled for GnRH. Arrows indicate migrating neurons; arrowheads indicate blood vessels; open triangles indicate the absence of migrating neurons; dotted lines indicate the FB boundary. OB, olfactory bulb. Scale bar: 100 µm. (D) GnRH neuron number in E14.5 heads of the indicated genotypes (mean±s.e.m.): control, 1246±46, n=6; Vegfa120/120, 854±21, n=5; Vegfa188/188, 1335±63, n=3; Vegfa120/188, 1314±58, n=3; t-test; ***P<0.001 compared with control.
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DEV115998F4: VEGF188 is sufficient to promote GnRH neuron survival. (A) GnRH neuron migration (blue dots). The neurons are born in the nasal placodes that give rise to the olfactory and vomeronasal epithelia (OE, VNO) and migrate along olfactory and vomeronasal axons (purple, Olf/VN) through the nasal compartment (NC) to reach the forebrain (FB). (B) Serum-starved GN11 cells were treated with DMEM or DMEM-containing serum, VEGF120, VEGF164 or VEGF188; cell death was visualised by propidium iodide staining (red); Hoechst staining (blue) identified the total number of cells. Scale bar: 25 µm. (C) Sagittal sections of E14.5 mouse heads of the indicated genotypes, immunolabelled for GnRH. Arrows indicate migrating neurons; arrowheads indicate blood vessels; open triangles indicate the absence of migrating neurons; dotted lines indicate the FB boundary. OB, olfactory bulb. Scale bar: 100 µm. (D) GnRH neuron number in E14.5 heads of the indicated genotypes (mean±s.e.m.): control, 1246±46, n=6; Vegfa120/120, 854±21, n=5; Vegfa188/188, 1335±63, n=3; Vegfa120/188, 1314±58, n=3; t-test; ***P<0.001 compared with control.
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.

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.

View Article: PubMed Central - PubMed

Affiliation: UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK.

Show MeSH
Related in: MedlinePlus