Title: The Chemokine SDF1a Coordinates Tissue Migration through the Spatially Restricted Activation of Cxcr7 and Cxcr4b
Abstract: Tissue migration is a collective behavior that plays a key role in the formation of many organ systems [1Lecaudey V. Gilmour D. Organizing moving groups during morphogenesis.Curr. Opin. Cell Biol. 2006; 18: 102-107Crossref PubMed Scopus (95) Google Scholar, 2Friedl P. Prespecification and plasticity: Shifting mechanisms of cell migration.Curr. Opin. Cell Biol. 2004; 16: 14-23Crossref PubMed Scopus (506) Google Scholar, 3Affolter M. Bellusci S. Itoh N. Shilo B. Thiery J.P. Werb Z. Tube or not tube: Remodeling epithelial tissues by branching morphogenesis.Dev. Cell. 2003; 4: 11-18Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar]. Although tissue movements are guided by extrinsic cues, in many contexts, their receptors need to be active only at the leading edge to ensure morphogenesis [4Cabernard C. Affolter M. Distinct roles for two receptor tyrosine kinases in epithelial branching morphogenesis in Drosophila.Dev. Cell. 2005; 9: 831-842Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar, 5Ghabrial A.S. Krasnow M.A. Social interactions among epithelial cells during tracheal branching morphogenesis.Nature. 2006; 441: 746-749Crossref PubMed Scopus (176) Google Scholar, 6Haas P. Gilmour D. Chemokine signaling mediates self-organizing tissue migration in the zebrafish lateral line.Dev. Cell. 2006; 10: 673-680Abstract Full Text Full Text PDF PubMed Scopus (354) Google Scholar, 7Shakya R. Watanabe T. Costantini F. The role of GDNF/Ret signaling in ureteric bud cell fate and branching morphogenesis.Dev. Cell. 2005; 8: 65-74Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar, 8Su M. Merz D.C. Killeen M.T. Zhou Y. Zheng H. Kramer J.M. Hedgecock E.M. Culotti J.G. Regulation of the UNC-5 netrin receptor initiates the first reorientation of migrating distal tip cells in Caenorhabditis elegans.Development. 2000; 127: 585-594PubMed Google Scholar]. This has led to the prevalent view that extrinsic signals exert their influence by controlling a small number of leader cells. The zebrafish lateral-line primordium is a cohesive cohort of over 100 cells that is guided through CXCR4-SDF1 signaling [9Ghysen A. Dambly-Chaudiere C. Development of the zebrafish lateral line.Curr. Opin. Neurobiol. 2004; 14: 67-73Crossref PubMed Scopus (188) Google Scholar, 10David N.B. Sapede D. Saint-Etienne L. Thisse C. Thisse B. Dambly-Chaudiere C. Rosa F.M. Ghysen A. Molecular basis of cell migration in the fish lateral line: Role of the chemokine receptor CXCR4 and of its ligand, SDF1.Proc. Natl. Acad. Sci. USA. 2002; 99: 16297-16302Crossref PubMed Scopus (253) Google Scholar, 11Li Q. Shirabe K. Kuwada J.Y. Chemokine signaling regulates sensory cell migration in zebrafish.Dev. Biol. 2004; 269: 123-136Crossref PubMed Scopus (105) Google Scholar]. Recent work has shown that Cxcr4b activity is only required in cells at the very tip, raising the question of what controls cell behavior within trailing regions [6Haas P. Gilmour D. Chemokine signaling mediates self-organizing tissue migration in the zebrafish lateral line.Dev. Cell. 2006; 10: 673-680Abstract Full Text Full Text PDF PubMed Scopus (354) Google Scholar]. Here, we present the first mutant in zebrafish SDF1a/CXCL12a and show, surprisingly, that the resultant phenotype is stronger than a null mutation in its cognate receptor, Cxcr4b, indicating the involvement of other SDF1a receptors. A candidate approach identified Cxcr7/RDC1, whose expression is restricted to cells behind the leading edge. Morpholino knockdown of Cxcr7 leads to a novel phenotype in which the migration of trailing cells is specifically affected, causing tissue stretching, a defect rescued by the reintroduction of wild-type cells specifically at the back of the primordium. Finally, we present evidence that Cxcr4b and Cxcr7 act independently to regulate group migration. We provide the first example where a single extrinsic guidance cue, SDF1a, directly controls the migration of both leading and trailing edges of a tissue through the activation of two independent receptors, CXCR4b and CXCR7.