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First published online January 25, 2008
doi: 10.1242/10.1242/dev.013623

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The netrin receptor UNC5B promotes angiogenesis in specific vascular beds

Sutip Navankasattusas^1,*, Kevin J. Whitehead^1,2,*, Arminda Suli³, Lise K. Sorensen¹, Amy H. Lim³, Jia Zhao¹, Kye Won Park^1,, Joshua D. Wythe^1,4, Kirk R. Thomas^1,5, Chi-Bin Chien^3,6, and Dean Y. Li^1,2,4,

¹ Program in Human Molecular Biology and Genetics, University of Utah, Salt Lake City, UT 84112, USA.
² Division of Cardiology, Department of Internal Medicine, University of Utah, Salt Lake City, UT 84112, USA.
³ Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, UT 84112, USA.
⁴ Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA.
⁵ Division of Hematology, Department of Internal Medicine, University of Utah, Salt Lake City, UT 84112, USA.
⁶ Brain Institute, University of Utah, Salt Lake City, UT 84112, USA.

Authors for correspondence (e-mails: chi-bin.chien{at}neuro.utah.edu; dean.li{at}hmbg.utah.edu)

Accepted 21 November 2007

There is emerging evidence that the canonical neural guidance factor netrin can also direct the growth of blood vessels. We deleted the gene encoding UNC5B, a receptor for the netrin family of guidance molecules, specifically within the embryonic endothelium of mice. The result is a profound structural and functional deficiency in the arterioles of the placental labyrinth, which leads first to flow reversal in the umbilical artery and ultimately to embryonic death. As this is the only detectable site of vascular abnormality in the mutant embryos, and because the phenotype cannot be rescued by a wild-type trophectoderm, we propose that UNC5B-mediated signaling is a specific and autonomous component of fetal-placental angiogenesis. Disruption of UNC5B represents a unique example of a mutation that acts solely within the fetal-placental vasculature and one that faithfully recapitulates the structural and physiological characteristics of clinical uteroplacental insufficiency. This pro-angiogenic, but spatially restricted requirement for UNC5B is not unique to murine development, as the knock-down of the Unc5b ortholog in zebrafish similarly results in the specific and highly penetrant absence of the parachordal vessel, the precursor to the lymphatic system.

Key words: Angiogenesis, Netrin, Placenta, UNC5B, Zebrafish, Mouse

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