Robo4 is a vascular-specific receptor that inhibits endothelial migration.
Guidance and patterning of axons are orchestrated by cell-surface receptors and ligands that provide directional cues. Interactions between the Robo receptor and Slit ligand families of proteins initiate signaling cascades that repel axonal outgrowth. Although the vascular and nervous systems grow as parallel networks, the mechanisms by which the vascular endothelial cells are guided to their appropriate positions remain obscure. We have identified a putative Robo homologue, Robo4, based on its differential expression in mutant mice with defects in vascular sprouting. In contrast to known neuronal Robo family members, the arrangement of the extracellular domains of Robo4 diverges significantly from that of all other Robo family members. Moreover, Robo4 is specifically expressed in the vascular endothelium during murine embryonic development. We show that Robo4 binds Slit and inhibits cellular migration in a heterologous expression system, analogous to the role of known Robo receptors in the nervous system. Immunoprecipitation studies indicate that Robo4 binds to Mena, a known effector of Robo-Slit signaling. Finally, we show that Robo4 is the only Robo family member expressed in primary endothelial cells and that application of Slit inhibits their migration. These data demonstrate that Robo4 is a bona fide member of the Robo family and may provide a repulsive cue to migrating endothelial cells during vascular development.
Park
Kye Won
KW
School of Medicine, University of Utah, Salt Lake City, UT 84112, USA.
Morrison
Clayton M
CM
Sorensen
Lise K
LK
Jones
Christopher A
CA
Rao
Yi
Y
Chien
Chi-Bin
CB
Wu
Jane Y
JY
Urness
Lisa D
LD
Li
Dean Y
DY
D030201:Activin Receptors, Type I / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D030301:Activin Receptors, Type II; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D002874:Chromosome Mapping; D004730:Endothelium, Vascular / Q000196:embryology*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010802:Phylogeny; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D015027:Zebrafish; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein
D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein; C425364:ACVRL1 protein, human; C498931:Acvrl1 protein, mouse