Mis-Regulation of SDF1-CXCR4 Signalling Impairs Early Cardiac Neural Crest Cell Migration Leading to Conotruncal Defects
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 colonise the gut but, so far, molecular mechanisms segregating these two populations and driving cardiac NC migration towards the heart have remained elusive.
Objective: Stromal-Derived-Factor1 (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 towards 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 while Sdf1 mis-expression results in their diversion from their normal pathway, indicating that SDF1 acts as a chemoattractant for cardiac NCs. These alterations of SDF1 signalling result in severe cardiovascular defects.
Conclusions: These data identify Sdf1 and its receptor Cxcr4 as candidate genes responsible for cardiac congenital pathologies in human.
- cardiac neural crest
- CXCR4 receptor
- SDF1 chemokine
- developmental biology
- cardiac development
- conotruncal defects genes
- Received March 8, 2013.
- Revision received July 8, 2013.
- Accepted July 9, 2013.