Lu et al. uncovered a role for a netrin UNC-5 receptor, a member of a protein family associated with development of the nervous system, in vascular morphogenesis. Like the nervous system, the circulatory system consists of an intricate network that is found throughout the body. Thus, it is perhaps not surprising that, during blood vessel development, the endothelial tip cells that lead the way to appropriate targets extend filopodia, just as neuronal growth cones do, and respond to many of the same attractive and repellant molecules. Netrins act through two families of receptors, with the deleted in colorectal cancer (DCC) family mediating attractive interactions and the UNC-5 family mediating repulsive interactions. Lu et al. used in situ hybridization as well as a reporter engineered into the Unc5b locus to show that Unc5b, which has had no clear role in mammals, was selectively expressed in the vasculature of embryonic and postnatal mice. More specifically, Unc5b was localized to arterial cells, some capillary endothelial cells, and endothelial tip cells. Unc5b inactivation in mice--or Unc5b or netrin1a knockdown in zebrafish--promoted increased branching of the vasculature, impaired pathfinding, and abnormal endothelial tip cell filopodial extension. In contrast, exposure to netrin-1 inhibited the in vitro migration of primary human umbilical artery endothelial cells (which strongly expressed UNC5B) but not of human umbilical vein endothelial cells (which showed less UNC5B expression). Further, netrin-1 stimulated the retraction of endothelial cell filopodia, an effect that depended on Unc5b expression. Thus, the authors propose that netrin-1, acting through UNC5B, inhibits branching in the developing--and perhaps the adult--vascular system.
X. Lu, F. le Noble, L. Yuan, Q. Jiang, B. de LaFarge, D. Sugiyama, C. Bréant, F. Claes, F. de Smet, J.-L. Thomas, M. Autiero, P. Carmeliet, M. Tessier-Lavigne, A. Eichmann, The netrin receptor UNC5B mediates guidance events controlling morphogenesis of the vascular system. Nature 432, 179-186 (2004). [Online Journal]