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.
Sierro
Frederic
F
Department of Immunology and Inflammation, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst NSW 2010, Australia.
Biben
Christine
C
Martínez-Muñoz
Laura
L
Mellado
Mario
M
Ransohoff
Richard M
RM
Li
Meizhang
M
Woehl
Blanche
B
Leung
Helen
H
Groom
Joanna
J
Batten
Marcel
M
Harvey
Richard P
RP
Martínez-A
Carlos
C
Mackay
Charles R
CR
Mackay
Fabienne
F
D000818:Animals; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism*; D036681:Fluorescence Recovery After Photobleaching; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology*; D006351:Heart Valves / Q000196:embryology; D006410:Hematopoiesis; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009024:Morphogenesis; D011485:Protein Binding; D054387:Receptors, CXCR; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*