Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 33, Pages 13782-13787Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1100341108
Keywords
angiogenesis; neurovascular link; neuronal migration; cerebellum
Categories
Funding
- Institut National de la Sante et de la Recherche Medicale
- Region Rhone-Alpes
- Ligue contre le Cancer
- Flemish government
- Fund for Scientific Research-Flemish government [G.0677.09, G.0201.07]
- Concerted Research Activities Katholieke Universiteit Leuven [GOA/2006/11]
- Belgian Science Policy [IUAP-P6/20, IUAP-P6/30]
- Association Francaise contre les Myopathies
- Geneeskundige Stichting Koningin Elisabeth (Queen Elizabeth Medical Foundation)
- Motor Neurone Disease Sssociation [70/130]
- Federation of European Biochemical Societies
- Fund of Scientific Research - Flanders Government
- Fondation pour la Recherche Medicale
- Agence Nationale de la Recherche [ANR-08-MNPS-030-01]
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NMDA type glutamate receptors (NMDARs) are best known for their role in synaptogenesis and synaptic plasticity. Much less is known about their developmental role before neurons form synapses. We report here that VEGF, which promotes migration of granule cells (GCs) during postnatal cerebellar development, enhances NMDAR-mediated currents and Ca2+ influx in immature GCs before synapse formation. The VEGF receptor Flk1 forms a complex with the NMDAR subunits NR1 and NR2B. In response to VEGF, the number of Flk1/NR2B coclusters on the cell surface increases. Stimulation of Flk1 by VEGF activates Src-family kinases, which increases tyrosine phosphorylation of NR2B. Inhibition of Src-family kinases abolishes the VEGF-dependent NR2B phosphorylation and amplification of NMDAR-mediated currents and Ca2+ influx in GCs. These findings identify VEGF as a modulator of NMDARs before synapse formation and highlight a link between an activity-independent neurovascular guidance cue (VEGF) and an activity-regulated neurotransmitter receptor (NMDAR).
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