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J. Biol. Chem., Vol. 281, Issue 16, 11347-11356, April 21, 2006

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Robo4 Signaling in Endothelial Cells Implies Attraction Guidance Mechanisms^*

Sukhbir Kaur¹², Maria Domenica Castellone¹, Victoria M. Bedell, Martha Konar, J. Silvio Gutkind, and Ramani Ramchandran³

From the Laboratory of Pathology, NCI, and the Cell Growth Regulation Section, Oral and Pharyngeal Cancer Branch, NIDCR, National Institutes of Health, Rockville, Maryland 20850

Roundabouts (robo) are cell-surface receptors that mediate repulsive signaling mechanisms at the central nervous system midline. However, robos may also mediate attraction mechanisms in the context of vascular development. Here, we have performed structure-function analysis of roundabout4 (Robo4), the predominant robo expressed in embryonic zebrafish vasculature and found by gain of function approaches in vitro that Robo4 activates Cdc42 and Rac1 Rho GTPases in endothelial cells. Indeed, complementary robo4 gene knockdown approaches in zebrafish embryos show lower amounts of active Cdc42 and Rac1 and angioblasts isolated from these knockdown embryos search actively for directionality and guidance cues. Furthermore, Robo4-expressing endothelial cells show morphology and phenotype, characteristic of Rho GTPase activation. Taken together, this study suggests that Robo4 mediates attraction-signaling mechanisms through Rho GTPases in vertebrate vascular guidance.

Received for publication, August 11, 2005 , and in revised form, February 15, 2006.

^* This work was supported in part by the Intramural Research Program of NCI, National Institutes of Health (NIH), Center for Cancer Research. We declare that we have no competing financial interests. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental movies 1-4.

¹ Both authors contributed equally to this work.

² A recipient of an NCI, NIH Cancer Research Training Award fellowship.

³ Recipient of NCI Scholar grant. To whom correspondence should be addressed: Laboratory of Pathology, NCI, NIH, Key West Facility, Room 320, 9610 Medical Center Drive, Rockville, MD 20850. Tel.: 301-402-9640; Fax: 301-402-4422; E-mail: ramchanr{at}mail.nih.gov.

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