Defective ALK5 signaling in the neural crest leads to increased postmigratory neural crest cell apoptosis and severe outflow tract defects

Jikui Wang,Vesa Kaartinen,Andre Nagy,Henry M Sucov,Marek Dudas,Jonas Larsson

doi:10.1186/1471-213x-6-51

Abstract

BackgroundCongenital cardiovascular diseases are the most common form of birth defects in humans. A substantial portion of these defects has been associated with inappropriate induction, migration, differentiation and patterning of pluripotent cardiac neural crest stem cells. While TGF-β-superfamily signaling has been strongly implicated in neural crest cell development, the detailed molecular signaling mechanisms in vivo are still poorly understood.ResultsWe deleted the TGF-β type I receptor Alk5 specifically in the mouse neural crest cell lineage. Failure in signaling via ALK5 leads to severe cardiovascular and pharyngeal defects, including inappropriate remodeling of pharyngeal arch arteries, abnormal aortic sac development, failure in pharyngeal organ migration and persistent truncus arteriosus. While ALK5 is not required for neural crest cell migration, our results demonstrate that it plays an important role in the survival of post-migratory cardiac neural crest cells.ConclusionOur results demonstrate that ALK5-mediated signaling in neural crest cells plays an essential cell-autonomous role in the pharyngeal and cardiac outflow tract development.

Highlights

Congenital cardiovascular diseases are the most common form of birth defects in humans
Cardiac neural crest cells (CNCCs) delaminate, undergo a phenotypic transformation from an epithelial to mesenchymal cell type, and migrate latero-ventrally into the 3rd, 4th and 6th pharyngeal arch arteries (PAAs), where they contribute to the formation of the smooth muscle cell layer of endothelial structures derived from the aortic arch arteries [1,2,3]
An indispensable role of cardiac neural crest cells (CNCCs) in the development of the cardiac outflow tract was originally demonstrated by pioneering studies of Kirby and coworkers [1], who showed that ablation of the cardiac neural crest (CNC) in the chick led to severe outflow tract (OFT) defects including persistent truncus arteriosus (PTA), mispatterning of the great vessels and outflow tract mal-alignments [5]

Summary

Introduction

Congenital cardiovascular diseases are the most common form of birth defects in humans. A substantial portion of these defects has been associated with inappropriate induction, migration, differentiation and patterning of pluripotent cardiac neural crest stem cells. A considerable percentage of cardiac birth defects is caused by a failure in normal migration, differentiation or patterning of the cardiac neural crest (CNC). This subset of pluripotent neural crest stem cells forms in the dorsal aspect of the neural tube at the level of the mid-otic placode to the third somite [1]. Neural crest-specific deletion of the BMP type I receptors Alk and Alk has been shown to lead to defective aortico-pulmonary septation, among other cardiac defects [12,13]

Methods

Results

Discussion

Conclusion