1. Department of Biological Sciences, Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA
2. INSERM U 36, Collège de France, 11 Place Marcelin Berthelot, 75005 Paris, France
3. CNRS UMR 7622, Université Pierre et Marie Curie, 9 Quai St Bernard, 75252 Paris, France
4. Center for Transgene Technology & Gene Therapy, Flanders Interuniversity Institute for Biotechnology (VIB), University of Leuven, Herestraat 49B-3000, Leuven, Belgium
5. Inserm U495, IFR Neurosciences, Hôpital de la Salpêtrière, Université Pierre et Marie Curie, 75651 Paris, France
6. These authors contributed equally to this work
7. Present addresses: College of Animal Science, South China Agricultural University, Guangzhou 510642, China (Q.J.); Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA (M.T.-L.)

Correspondence to: Marc Tessier-Lavigne^1,7Anne Eichmann² Email: anne.eichmann@college-de-france.fr
Email: tessier-lavigne.marc@gene.com
Zebrafish Unc5b is deposited in GenBank under accession number AY764274.

Abstract

Blood vessels and nerves are complex, branched structures that share a high degree of anatomical similarity. Guidance of vessels and nerves has to be exquisitely regulated to ensure proper wiring of both systems. Several regulators of axon guidance have been identified and some of these are also expressed in endothelial cells; however, the extent to which their guidance functions are conserved in the vascular system is still incompletely understood. We show here that the repulsive netrin receptor UNC5B is expressed by endothelial tip cells of the vascular system. Disruption of the Unc5b gene in mice, or of Unc5b or netrin-1a in zebrafish, leads to aberrant extension of endothelial tip cell filopodia, excessive vessel branching and abnormal navigation. Netrin-1 causes endothelial filopodial retraction, but only when UNC5B is present. Thus, UNC5B functions as a repulsive netrin receptor in endothelial cells controlling morphogenesis of the vascular system.

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