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
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DOI：
10.1242/dev.126573
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发表时间：
2016-02-15
期刊：
影响因子：
4.6
通讯作者：
Fournier-Thibault, Claire
中科院分区：
文献类型：
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作者：
Escot, Sophie;Blavet, Cedrine;Fournier-Thibault, Claire
DiGeorge综合征（DGS）是一种引起心脏流出道畸形、颅面畸形、胸腺发育不全和精神障碍的先天性疾病。它是由神经嵴细胞（NC）发育缺陷引起的，神经嵴细胞（NC）定植于咽弓并有助于下颌、颈部和心脏组织。虽然TBX 1已被确定为在人类患者和小鼠模型中观察到的缺陷的主要基因，但DGS病因学的分子机制尚不清楚。最近的证据表明，SDF 1/CXCR 4轴涉及NC趋化性指导和受损的小鼠DGS模型的皮质中间神经元，促使我们寻找Tbx 1，Sdf 1（Cxcl 12）和Cxcr 4之间的遗传相互作用在咽部NC和调查的影响，改变CXCR 4信号对个体发育的衍生物，这是影响DGS。在这里，我们提供的证据表明，CXCR 4和SDF 1的遗传下游的Tbx 1在咽NC的发展和减少CXCR 4信号传导导致误路由的咽NC在鸡和戏剧性的形态学改变在下颌骨骨骼，胸腺和颅感觉神经节。因此，我们的研究结果支持SDF 1/CXCR 4轴在DGS病因学中起关键作用的可能性。
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.