Matrix-binding vascular endothelial growth factor (VEGF) isoforms guide granule cell migration in the cerebellum via VEGF receptor Flk1.
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.
Vesalius Research Center, Vlaams Instituut voor Biotechnologie, Vesalius Research Center, Katholieke Universiteit Leuven, Belgium.
Carmen
C
Ruiz de Almodovar
Cathy
C
Coulon
Paul Antoine
PA
Salin
Ellen
E
Knevels
Naura
N
Chounlamountri
Koen
K
Poesen
Karlien
K
Hermans
Diether
D
Lambrechts
Katie
K
Van Geyte
Joke
J
Dhondt
Tom
T
Dresselaers
Julie
J
Renaud
Julian
J
Aragones
Serena
S
Zacchigna
Ilse
I
Geudens
David
D
Gall
Stijn
S
Stroobants
Mireille
M
Mutin
Karel
K
Dassonville
Erik
E
Storkebaum
Bénédicte F
BF
Jordan
Ulf
U
Eriksson
Lieve
L
Moons
Rudi
R
D'Hooge
Jody J
JJ
Haigh
Marie-Françoise
MF
Belin
Serge
S
Schiffmann
Paul
P
Van Hecke
Bernard
B
Gallez
Stefan
S
Vinckier
Alain
A
Chédotal
Jérôme
J
Honnorat
Nicole
N
Thomasset
Peter
P
Carmeliet
Claire
C
Meissirel
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D020439:Growth Cones / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D020033:Protein Isoforms / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism*
D020033:Protein Isoforms; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2