title: Disruption of CXCR4 signaling in pharyngeal neural crest cells causes DiGeorge syndrome-like malformations.
abstract: 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.
authors.affiliation: Université Pierre et Marie Curie, Laboratoire de Biologie du Développement, Paris 75252 Cedex 5, France CNRS, Laboratoire de Biologie du Développement, Paris 75252 Cedex 5, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Escot
authors.affiliation: Université Pierre et Marie Curie, Laboratoire de Biologie du Développement, Paris 75252 Cedex 5, France CNRS, Laboratoire de Biologie du Développement, Paris 75252 Cedex 5, France.
authors.forename: Cédrine
authors.initials: C
authors.lastname: Blavet
authors.affiliation: Aix Marseille Université, GMGF UMRS910, Faculté de Médecine, 27 Bd Jean Moulin, Marseille 13385, France Inserm U910, Faculté de Médecine, 27 Bd Jean Moulin, Marseille 13005, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Faure
authors.affiliation: Aix Marseille Université, GMGF UMRS910, Faculté de Médecine, 27 Bd Jean Moulin, Marseille 13385, France Inserm U910, Faculté de Médecine, 27 Bd Jean Moulin, Marseille 13005, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Zaffran
authors.affiliation: Université Pierre et Marie Curie, Laboratoire de Biologie du Développement, Paris 75252 Cedex 5, France CNRS, Laboratoire de Biologie du Développement, Paris 75252 Cedex 5, France claire.thibault@upmc.fr jean-loup.duband@inserm.fr.
authors.forename: Jean-Loup
authors.initials: JL
authors.lastname: Duband
authors.affiliation: Université Pierre et Marie Curie, Laboratoire de Biologie du Développement, Paris 75252 Cedex 5, France CNRS, Laboratoire de Biologie du Développement, Paris 75252 Cedex 5, France claire.thibault@upmc.fr jean-loup.duband@inserm.fr.
authors.forename: Claire
authors.initials: C
authors.lastname: Fournier-Thibault
mesh_terms: D000818:Animals; D001934:Branchial Region / Q000473:pathology*; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000378:metabolism; D019465:Craniofacial Abnormalities / Q000473:pathology; D004062:DiGeorge Syndrome / Q000378:metabolism* / Q000473:pathology; D008817:Mice, Mutant Strains; D009432:Neural Crest / Q000378:metabolism*; D009474:Neurons / Q000473:pathology; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000378:metabolism
chemical_list: D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D020825:T-Box Domain Proteins; C491573:Tbx1 protein, mouse
keywords: CXCR4; Chick; DiGeorge syndrome; Mouse; Neural crest; SDF1; TBX1