Vascular endothelial growth factor receptor 3 directly regulates murine neurogenesis
Por:
C. CALVO, R. FONTAINE, J. SOUEID, T. TAMMELA, T. MAKINEN, C. ALFARO-CERVELLO, F. BONNAUD, A. MIGUEZ, L. BENHAIM, Y. XU, M. BARALLOBRE, I. MOUTKINE, J. LYYTIKKA, T. TATLISUMAK, B. PYTOWSKI, B. ZALC, W. RICHARDSON, N. KESSARIS, J. GARCIA-VERDUGO, K. ALITALO, A. EICHMANN and J. THOMAS
Publicada:
15 abr 2011
Resumen:
Neural stem cells (NSCs) are slowly dividing astrocytes that are intimately associated with capillary endothelial cells in the subventricular zone (SVZ) of the brain. Functionally, members of the vascular endothelial growth factor (VEGF) family can stimulate neurogenesis as well as angiogenesis, but it has been unclear whether they act directly via VEGF receptors (VEGFRs) expressed by neural cells, or indirectly via the release of growth factors from angiogenic capillaries. Here, we show that VEGFR-3, a receptor required for lymphangiogenesis, is expressed by NSCs and is directly required for neurogenesis. Vegfr3::YFP reporter mice show VEGFR-3 expression in multipotent NSCs, which are capable of self-renewal and are activated by the VEGFR-3 ligand VEGF-C in vitro. Overexpression of VEGF-C stimulates VEGFR-3-expressing NSCs and neurogenesis in the SVZ without affecting angiogenesis. Conversely, conditional deletion of Vegfr3 in neural cells, inducible deletion in subventricular astrocytes, and blocking of VEGFR-3 signaling with antibodies reduce SVZ neurogenesis. Therefore, VEGF-C/VEGFR-3 signaling acts directly on NSCs and regulates adult neurogenesis, opening potential approaches for treatment of neurodegenerative diseases.
Filiaciones:
C. CALVO:
Univ Paris 06, Ctr Rech, Inst Cerveau & Moelle Epiniere, UMR S975, F-75651 Paris, France
INSERM, U975, F-75651 Paris, France
CNRS, UMR 7225, F-75651 Paris, France
R. FONTAINE:
Univ Paris 06, Ctr Rech, Inst Cerveau & Moelle Epiniere, UMR S975, F-75651 Paris, France
INSERM, U975, F-75651 Paris, France
CNRS, UMR 7225, F-75651 Paris, France
J. SOUEID:
Univ Paris 06, Ctr Rech, Inst Cerveau & Moelle Epiniere, UMR S975, F-75651 Paris, France
INSERM, U975, F-75651 Paris, France
CNRS, UMR 7225, F-75651 Paris, France
T. TAMMELA:
Univ Helsinki, Biomedicum Helsinki, Mol Canc Biol Lab, FI-00290 Helsinki, Finland
Univ Helsinki, Haartman Inst, Dept Pathol, FI-00290 Helsinki, Finland
T. MAKINEN:
Univ Helsinki, Biomedicum Helsinki, Mol Canc Biol Lab, FI-00290 Helsinki, Finland
Univ Helsinki, Haartman Inst, Dept Pathol, FI-00290 Helsinki, Finland
C. ALFARO-CERVELLO:
CIBERNED, Lab Morfol Celular, Ctr Invest Principe Felipe, Valencia 46013, Spain
F. BONNAUD:
PerkinElmer, Cellular Imaging & Anal, Coventry HP9 2FX, W Midlands, England
A. MIGUEZ:
Univ Paris 06, Ctr Rech, Inst Cerveau & Moelle Epiniere, UMR S975, F-75651 Paris, France
INSERM, U975, F-75651 Paris, France
CNRS, UMR 7225, F-75651 Paris, France
L. BENHAIM:
Univ Paris 06, Ctr Rech, Inst Cerveau & Moelle Epiniere, UMR S975, F-75651 Paris, France
INSERM, U975, F-75651 Paris, France
CNRS, UMR 7225, F-75651 Paris, France
Y. XU:
Coll France, CIRB, F-75005 Paris, France
M. BARALLOBRE:
UPF, Ctr Genom Regulat, Barcelona 08003, Spain
CIBER Enfermedades Raras, Barcelona 08003, Spain
I. MOUTKINE:
Univ Paris 06, Ctr Rech, Inst Cerveau & Moelle Epiniere, UMR S975, F-75651 Paris, France
INSERM, U975, F-75651 Paris, France
CNRS, UMR 7225, F-75651 Paris, France
J. LYYTIKKA:
Univ Helsinki, Cent Hosp, Dept Neurol, Expt MRI Lab, FI-00290 Helsinki, Finland
T. TATLISUMAK:
Univ Helsinki, Cent Hosp, Dept Neurol, Expt MRI Lab, FI-00290 Helsinki, Finland
B. PYTOWSKI:
ImClone Syst, New York, NY 10016 USA
B. ZALC:
Univ Paris 06, Ctr Rech, Inst Cerveau & Moelle Epiniere, UMR S975, F-75651 Paris, France
INSERM, U975, F-75651 Paris, France
CNRS, UMR 7225, F-75651 Paris, France
AP HP, F-75651 Paris, France
W. RICHARDSON:
UCL, Wolfson Inst Biomed Res, London WC1E 6BT, England
UCL, Res Dept Cell & Dev Biol, London WC1E 6BT, England
N. KESSARIS:
UCL, Wolfson Inst Biomed Res, London WC1E 6BT, England
UCL, Res Dept Cell & Dev Biol, London WC1E 6BT, England
:
CIBERNED, Lab Morfol Celular, Ctr Invest Principe Felipe, Valencia 46013, Spain
Univ Valencia, Inst Cavanilles, Lab Neurobiol Comparada, Valencia 46980, Spain
K. ALITALO:
Univ Helsinki, Biomedicum Helsinki, Mol Canc Biol Lab, FI-00290 Helsinki, Finland
Univ Helsinki, Haartman Inst, Dept Pathol, FI-00290 Helsinki, Finland
A. EICHMANN:
Coll France, CIRB, F-75005 Paris, France
Yale Univ, Sch Med, Dept Cardiol, New Haven, CT 06511 USA
J. THOMAS:
Univ Paris 06, Ctr Rech, Inst Cerveau & Moelle Epiniere, UMR S975, F-75651 Paris, France
INSERM, U975, F-75651 Paris, France
CNRS, UMR 7225, F-75651 Paris, France
AP HP, F-75651 Paris, France
Yale Univ, Sch Med, Dept Neurol, New Haven, CT 06511 USA
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