Proc Natl Acad Sci U S A 2007 Sep 11;104(37):14759-64. Epub 2007 Se
Batten, M; Biben, C; Groom, J; Harvey, RP; Leung, H; Li, M; Mackay, CR; Mackay, F.; Martínez-A, C; Martínez-Muñoz, L; Mellado, M; Ransohoff, RM; Sierro, F; Woehl, B
Department of Immunology and Inflammation, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst NSW 2010, Australia.
Chemotactic cytokines (chemokines) attract immune cells, although their original evolutionary role may relate more closely with embryonic development. We noted differential expression of the chemokine receptor CXCR7 (RDC-1) on marginal zone B cells, a cell type associated with autoimmune diseases. We generated Cxcr7(-/-) mice but found that CXCR7 deficiency had little effect on B cell composition. However, most Cxcr7(-/-) mice died at birth with ventricular septal defects and semilunar heart valve malformation. Conditional deletion of Cxcr7 in endothelium, using Tie2-Cre transgenic mice, recapitulated this phenotype. Gene profiling of Cxcr7(-/-) heart valve leaflets revealed a defect in the expression of factors essential for valve formation, vessel protection, or endothelial cell growth and survival. We confirmed that the principal chemokine ligand for CXCR7 was CXCL12/SDF-1, which also binds CXCR4. CXCL12 did not induce signaling through CXCR7; however, CXCR7 formed functional heterodimers with CXCR4 and enhanced CXCL12-induced signaling. Our results reveal a specialized role for CXCR7 in endothelial biology and valve development and highlight the distinct developmental role of evolutionary conserved chemokine receptors such as CXCR7 and CXCR4.