An Essential Role of the Cytoplasmic Tail of CXCR4 in G-Protein Signaling and Organogenesis

Cronshaw, Darran G.; Nie, Yong; Waite, Janelle; Zou, Yong-Rui

doi:10.1371/journal.pone.0015397

Cited by 19 publications

(19 citation statements)

References 52 publications

(50 reference statements)

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“…Using in ovo electroporation, we expressed in pharyngeal NCs either a miRNA against Cxcr4 (miRNA-Cxcr4, Fig. S5) or a dominant-negative form of Cxcr4 (DN-CXCR4) lacking the C-terminus sequences necessary for chemotactic migration (Ahr et al, 2005;Cronshaw et al, 2010). First, we searched for craniofacial dysmorphogenesis due to palate and jaw anomalies, a prominent trait of DGS patients (Fukui et al, 2000;Karpinski et al, 2014).…”

Section: Resultsmentioning

confidence: 99%

Disruption of CXCR4 signaling in pharyngeal neural crest cells causes DiGeorge syndrome-like malformations

et al. 2016

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DiGeorge syndrome (DGS) is a congenital disease causing cardiac outflow tract anomalies, craniofacial dysmorphogenesis, thymus hypoplasia, and mental disorders. It results from defective development of neural crest cells (NCs) that colonize the pharyngeal arches and contribute to lower jaw, neck and heart tissues. Although TBX1 has been identified as the main gene accounting for the defects observed in human patients and mouse models, the molecular mechanisms underlying DGS etiology are poorly identified. The recent demonstrations that the SDF1/CXCR4 axis is implicated in NC chemotactic guidance and impaired in cortical interneurons of mouse DGS models prompted us to search for genetic interactions between Tbx1, Sdf1 (Cxcl12) and Cxcr4 in pharyngeal NCs and to investigate the effect of altering CXCR4 signaling on the ontogeny of their derivatives, which are affected in DGS. Here, we provide evidence that Cxcr4 and Sdf1 are genetically downstream of Tbx1 during pharyngeal NC development and that reduction of CXCR4 signaling causes misrouting of pharyngeal NCs in chick and dramatic morphological alterations in the mandibular skeleton, thymus and cranial sensory ganglia. Our results therefore support the possibility of a pivotal role for the SDF1/CXCR4 axis in DGS etiology.

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Section: Resultsmentioning

confidence: 99%

Disruption of CXCR4 signaling in pharyngeal neural crest cells causes DiGeorge syndrome-like malformations

et al. 2016

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“…7,8 However, the complete deletion of the Cxcr4 C-tail leads to a loss of G protein-dependent function that causes developmental defects similar to those of Cxcr4-null mice. 19 This suggests that the remaining residues in the C-tail of WS-associated CXCR4 mutants that are targeted by numerous regulators 8,9,18 contribute to the enhanced CXCL12-dependent signaling. In lysates from WT mice, Cxcr4 ϩ/1013 mice, and Cxcr4 1013/1013 mice obtained by intercrossing heterozygous mice, immunodetection of Cxcr4 similarly revealed 1 band, suggesting that mutant and WT receptors cannot be distinguished in size (supplemental Figure 1D).…”

Section: Cxcr4 ؉/1013 Leukocytes Exhibit a Gain Of Cxcr4 Functionmentioning

confidence: 99%

Proper desensitization of CXCR4 is required for lymphocyte development and peripheral compartmentalization in mice

Balabanian

Brotin

Biajoux

et al. 2012

Blood

107

154

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Desensitization controls G protein-dependent signaling of chemokine receptors. We investigate the physiologic implication of this process for CXCR4 in a mouse model harboring a heterozygous mutation of the Cxcr4 gene, which engenders a desensitization-resistant receptor. Such anomaly is linked to the warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome, a human rare combined immunodeficiency. Cxcr4(+/mutant(1013)) mice display leukocytes with enhanced responses to Cxcl12 and exhibit leukopenia as reported in patients. Treatment with CXCL12/CXCR4 antagonists transiently reverses blood anomalies, further demonstrating the causal role of the mutant receptor in the leukopenia. Strikingly, neutropenia occurs in a context of normal bone marrow architecture and granulocyte lineage maturation, indicating a minor role for Cxcr4-dependent signaling in those processes. In contrast, Cxcr4(+/1013) mice show defective thymopoiesis and B-cell development, accounting for circulating lymphopenia. Concomitantly, mature T and B cells are abnormally compartmentalized in the periphery, with a reduction of primary follicles in the spleen and their absence in lymph nodes mirrored by an unfurling of the T-cell zone. These mice provide a model to decipher the role of CXCR4 desensitization in the homeostasis of B and T cells and to investigate which manifestations of patients with WHIM syndrome may be overcome by dampening the gain of CXCR4 function.

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“…Because SDF1 signaling is known to regulate both chemotactic migration and cell survival, 19 we overexpressed a construct encoding a dominant-negative form of Cxcr4 (DN-Cxcr4), in which the C-tail of the molecule was deleted. CXCR4 C-tail has been shown to be dispensable for SDF1-dependent survival but critical for chemotaxis, 20,21 allowing it to discriminate between SDF1 activities during cardiac NC migration. HNK1 immunolabeling revealed that 15 hpe, NCs expressing the DN-Cxcr4 were lagging behind the nonelectroporated NCs ( Figure 4A and 4B).…”

Section: Loss Of Cxcr4 Signaling Leads To Defective Cardiac Nc Migrationmentioning

confidence: 99%

“…It has been suggested that CXCR4 is involved in chemotaxis and CXCR7 in survival, 24 but other studies also proposed that both processes may be controlled by CXCR4. 25 In addition, biochemical studies showed that the CXCR4 C-terminal-tail is dispensable for activation of the Jak2/ STAT3 pathway involved in SDF1-dependent survival 20 or for integrin-mediated adhesion, 21 but is critical for chemotaxis. 20 Our results show that CXCR4, but not CXCR7, is expressed in cardiac NCs during their initial migration and that CXCR4 downregulation by miRNA leads to their apoptosis, whereas a dominant-negative form of CXCR4 lacking its C-terminal domain induces their misrouting without causing cell death, arguing for a role of CXCR4 in controlling both events in cardiac NCs.…”

Section: Sdf1 Drives Cardiac Nc Migration and Survival Through The CXmentioning

confidence: 99%

Misregulation of SDF1-CXCR4 Signaling Impairs Early Cardiac Neural Crest Cell Migration Leading to Conotruncal Defects

Escot

Blavet

Härtle

et al. 2013

Circulation Research

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Rationale: Cardiac neural crest cells (NCs) contribute to heart morphogenesis by giving rise to a variety of cell types from mesenchyme of the outflow tract, ventricular septum, and semilunar valves to neurons of the cardiac ganglia and smooth muscles of the great arteries. Failure in cardiac NC development results in outflow and ventricular septation defects commonly observed in congenital heart diseases. Cardiac NCs derive from the vagal neural tube, which also gives rise to enteric NCs that colonize the gut; however, so far, molecular mechanisms segregating these 2 populations and driving cardiac NC migration toward the heart have remained elusive. Objective: Stromal-derived factor-1 (SDF1) is a chemokine that mediates oriented migration of multiple embryonic cells and mice deficient for Sdf1 or its receptors, Cxcr4 and Cxcr7 , exhibit ventricular septum defects, raising the possibility that SDF1 might selectively drive cardiac NC migration toward the heart via a chemotactic mechanism. Methods and Results : We show in the chick embryo that Sdf1 expression is tightly coordinated with the progression of cardiac NCs expressing Cxcr4 . Cxcr4 loss-of-function causes delayed migration and enhanced death of cardiac NCs, whereas Sdf1 misexpression results in their diversion from their normal pathway, indicating that SDF1 acts as a chemoattractant for cardiac NCs. These alterations of SDF1 signaling result in severe cardiovascular defects. Conclusions: These data identify Sdf1 and its receptor Cxcr4 as candidate genes responsible for cardiac congenital pathologies in human.

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An Essential Role of the Cytoplasmic Tail of CXCR4 in G-Protein Signaling and Organogenesis

Cited by 19 publications

References 52 publications

Disruption of CXCR4 signaling in pharyngeal neural crest cells causes DiGeorge syndrome-like malformations

Disruption of CXCR4 signaling in pharyngeal neural crest cells causes DiGeorge syndrome-like malformations

Proper desensitization of CXCR4 is required for lymphocyte development and peripheral compartmentalization in mice

Misregulation of SDF1-CXCR4 Signaling Impairs Early Cardiac Neural Crest Cell Migration Leading to Conotruncal Defects

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