1. J Neurosci. 2010 Nov 10;30(45):15052-66.

Matrix-binding vascular endothelial growth factor (VEGF) isoforms guide granule
cell migration in the cerebellum via VEGF receptor Flk1.

Ruiz de Almodovar C, Coulon C, Salin PA, Knevels E, Chounlamountri N, Poesen K,
Hermans K, Lambrechts D, Van Geyte K, Dhondt J, Dresselaers T, Renaud J, Aragones
J, Zacchigna S, Geudens I, Gall D, Stroobants S, Mutin M, Dassonville K,
Storkebaum E, Jordan BF, Eriksson U, Moons L, D'Hooge R, Haigh JJ, Belin MF,
Schiffmann S, Van Hecke P, Gallez B, Vinckier S, Chédotal A, Honnorat J,
Thomasset N, Carmeliet P, Meissirel C.

Vesalius Research Center, Vlaams Instituut voor Biotechnologie, Vesalius Research
Center, Katholieke Universiteit Leuven, Belgium.

Vascular endothelial growth factor (VEGF) regulates angiogenesis, but also has
important, yet poorly characterized roles in neuronal wiring. Using several
genetic and in vitro approaches, we discovered a novel role for VEGF in the
control of cerebellar granule cell (GC) migration from the external granule cell 
layer (EGL) toward the Purkinje cell layer (PCL). GCs express the VEGF receptor
Flk1, and are chemoattracted by VEGF, whose levels are higher in the PCL than
EGL. Lowering VEGF levels in mice in vivo or ectopic VEGF expression in the EGL
ex vivo perturbs GC migration. Using GC-specific Flk1 knock-out mice, we provide 
for the first time in vivo evidence for a direct chemoattractive effect of VEGF
on neurons via Flk1 signaling. Finally, using knock-in mice expressing single
VEGF isoforms, we show that pericellular deposition of matrix-bound VEGF isoforms
around PC dendrites is necessary for proper GC migration in vivo. These findings 
identify a previously unknown role for VEGF in neuronal migration.


PMID: 21068311 [PubMed - indexed for MEDLINE]