Atypical Chemokine Receptor 3 Generates Guidance Cues for CXCL12-Mediated Endothelial Cell Migration.

Chemokine receptor CXCR4, its ligand stromal cell-derived factor-1 (CXCL12) and the decoy receptor atypical chemokine receptor 3 (ACKR3, also named CXCR7), are involved in the guidance of migrating cells in different anatomical districts. Here, we investigated the role of the zebrafish ortholog in the vascularization process during embryonic development. Bioinformatics and functional analyses confirmed that is a CXCL12-binding ortholog of human . is transcribed in the endoderm of zebrafish embryos during epiboly and is expressed in a wide range of tissues during somitogenesis, including central nervous system and somites. Between 18 somite and 26 h-post fertilization stages, the broad somitic expression of becomes restricted to the basal part of the somites. After knockdown, intersomitic vessels (ISVs) lose the correct direction of migration and are characterized by the presence of aberrant sprouts and ectopic filopodia protrusions, showing downregulation of the tip/stalk cell marker . In addition, morphants show significant alterations of lateral dorsal aortae formation. In keeping with a role for in endothelial cell guidance, CXCL12 gradient generated by expression in CHO cell transfectants guides human endothelial cell migration in an cell co-culture chemotaxis assay. Our results demonstrate that plays a non-redundant role in the guidance of sprouting endothelial cells during vascular development in zebrafish. Moreover, ACKR3 scavenging activity generates guidance cues for the directional migration of CXCR4-expressing human endothelial cells in response to CXCL12.