Misregulation of SDF1-CXCR4 Signaling Impairs Early Cardiac Neural Crest Cell Migration Leading to Conotruncal Defects
Misregulation of SDF1-CXCR4 Signaling Impairs Early Cardiac Neural Crest Cell Migration Leading to Conotruncal Defects
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DOI：
10.1161/circresaha.113.301333
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发表时间：
2013-08-16
影响因子：
20.1
通讯作者：
Fournier-Thibault, Claire
中科院分区：
文献类型：
--
作者：
Escot, Sophie;Blavet, Cedrine;Fournier-Thibault, Claire
理论基础：心脏神经脊细胞(NCS)通过从流出道间充质、室间隔和半月瓣到心脏神经节和大动脉平滑肌肉的神经元产生各种类型的细胞来促进心脏的形态发生。心脏NC发育失败导致流出和室间隔缺陷，常见于先天性心脏病。心脏NC来源于迷走神经管，迷走神经管也导致肠道NC定植于肠道；然而，迄今为止，分离这两个群体并推动心脏NC向心脏迁移的分子机制尚不清楚。目的：基质衍生因子-1(SDF1)是一种趋化因子，介导多个胚胎细胞的定向迁移，而缺乏SDF1或其受体CXCR4和CXCR7的小鼠表现出室间隔缺陷，这增加了SDF1可能通过趋化机制选择性地推动心脏NC向心脏迁移的可能性。方法和结果：我们在鸡胚胎中证明SDF1的表达与心脏NCCS表达XCR4的进程密切协调。CXCR4功能丧失导致心脏NCS迁移延迟和死亡增加，而SDF1的错误表达导致其偏离正常途径，表明SDF1对心脏NCS具有趋化作用。结论：SDF1及其受体CXCR4是人类心脏先天性疾病的候选基因。
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.