Disrupted cardiac development but normal hematopoiesis in mice deficient in the second CXCL12/SDF-1 receptor, CXCR7
Copyright policy )Disrupted cardiac development but normal hematopoiesis in mice deficient in the second CXCL12/SDF-1 receptor, CXCR7
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.
- Cleveland Clinic United States
- Spanish National Research Council Spain
- GENENTECH INC United States
- National Center for Biotechnology Spain
- Garvan Institute of Medical Research Australia
Mice, Knockout, Receptors, CXCR, Gene Expression Profiling, Gene Expression Regulation, Developmental, Heart, Mice, Transgenic, Heart Valves, Immunohistochemistry, Chemokine CXCL12, Hematopoiesis, Receptors, G-Protein-Coupled, Mice, Morphogenesis, Animals, Chemokines, CXC, Fluorescence Recovery After Photobleaching, Protein Binding
Mice, Knockout, Receptors, CXCR, Gene Expression Profiling, Gene Expression Regulation, Developmental, Heart, Mice, Transgenic, Heart Valves, Immunohistochemistry, Chemokine CXCL12, Hematopoiesis, Receptors, G-Protein-Coupled, Mice, Morphogenesis, Animals, Chemokines, CXC, Fluorescence Recovery After Photobleaching, Protein Binding
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