Early postnatal lethality and cardiovascular defects in CXCR7‐deficient mice

Abstract

CXCR7 is a G-protein coupled receptor that was recently deorphanized and shown to have SDF1 and I-TAC as high affinity ligands. Here we describe the characterization of CXCR7-deficient mice that were generated to further investigate the function of this receptor in vivo. Expression analysis using a LacZ reporter knockin revealed that postnatally Cxcr7 was specifically expressed in cardiomyocytes, vascular endothelial cells of the lung and heart, the cerebral cortex and in osteocytes of the bone. Adult tissues revealed high expression in cardiomyocytes and osteocytes. The observation that 70% of the Cxcr7-/- mice died in the first week after birth coincides with expression of Cxcr7 in vascular endothelial cells and in cardiomyocytes. An important role of CXCR7 in the cardiovascular system was further supported by the observation that hearts of the Cxcr7-/- mice were enlarged, showed myocardial degeneration and fibrosis of postnatal origin, and hyperplasia of embryonic origin. Despite high expression in osteocytes no apparent bone phenotype was observed, neither in combination with ovariectomy nor orchidectomy. Thus as CXCR7 does not seem to play an important role in bone our data indicate an important function of CXCR7 in the cardiovascular system during multiple steps of development.

CXCR7 influences the migration of B cells during maturation

“…Thus, CXCR7 could be envisaged as a marker for B cells exiting the GC and possibly of extrafollicular plasmablasts. Such role for CXCR7 as marker for GC egress would have been difficult to observe in mice with targeted deletion of CXCR7, because the animals were reported to die at birth and therefore immune responses could not be studied [36,55]. A possible mechanism for CXCR7-dependent modulation of CXCR4 function could be receptor heterodimerization [36][37][38].…”

Antagonism of CXCR7 attenuates chronic hypoxia–induced pulmonary hypertension

“…Although expression patterns for this receptor remain controversial (8,9,13,25,26), there is general agreement that it can be expressed on the membranes of endothelial cells and smooth muscle cells in various tissues (9,16,20,27). The ligands for CXCR7 are CXCL11 and SDF-1 (ref.…”

“…Indeed, some studies suggest that CXCR7 is a nonsignaling, decoy receptor that scavenges and degrades chemokine ligands (28,29). However, although there is evidence to suggest that CXCR7 does not signal through classical G-protein-mediated pathways (14,28), many studies have demonstrated an important role of this receptor in physiological and pathological processes (9,25,(30)(31)(32). CXCR7-deficient mice were shown to die within the first week after birth due to cardiovascular malformations (25).…”

“…However, although there is evidence to suggest that CXCR7 does not signal through classical G-protein-mediated pathways (14,28), many studies have demonstrated an important role of this receptor in physiological and pathological processes (9,25,(30)(31)(32). CXCR7-deficient mice were shown to die within the first week after birth due to cardiovascular malformations (25). Moreover, within several organ systems, CXCR7 has been shown to play a distinctive role in the adhesion, proliferation, and migration of endothelial, smooth muscle, and progenitor cells (20,31).…”

Sprouting of Nervous Fibers and Upregulation of C‐X‐C Chemokine Receptor Type 4 Expression in Hippocampal Formation of Rats with Enhanced Spatial Learning and Memory

“…Supporting evidence has revealed that CXCR7 is involved in tumorigenesis (Maksym et al, 2009). CXCR7 knockout mice have demonstrated cardiac valve malformation or enlarged hearts (Leung et al, 2007;Gerrits et al, 2008), and no brain defects were observed in these animals. CXCR7 mRNA expression was considerably increased in the granular layer and in the CA3 pyramidal cell layer in the postnatal rat brain (Schönemeier et al, 2008).…”