Loss of MicroRNAs in Neural Crest Leads to Cardiovascular Syndromes Resembling Human Congenital Heart Defects

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 30; no. 12; pp. 2575 - 2586
• Main Authors: Huang, Zhan-Peng, Chen, Jian-Fu, Regan, Jenna N, Maguire, Colin T, Tang, Ru-Hang, Rong Dong, Xiu, Majesky, Mark W, Wang, Da-Zhi
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.12.2010; Lippincott Williams & Wilkins
• Subjects: Abnormalities, Multiple - embryology; Abnormalities, Multiple - genetics; Abnormalities, Multiple - pathology; Adaptor Proteins, Signal Transducing; Animals; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cell Death; Cell Differentiation; Cell Movement; Cell Survival; Craniofacial Abnormalities - embryology; Craniofacial Abnormalities - genetics; Craniofacial Abnormalities - pathology; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Embryo, Mammalian - abnormalities; Embryo, Mammalian - metabolism; Extracellular Signal-Regulated MAP Kinases - metabolism; Gene Expression Regulation, Developmental; Genotype; Heart Defects, Congenital - embryology; Heart Defects, Congenital - genetics; Heart Defects, Congenital - pathology; Humans; Injuries of the limb. Injuries of the spine; Intracellular Signaling Peptides and Proteins; Medical sciences; Membrane Proteins - metabolism; Mice; Mice, Knockout; MicroRNAs - metabolism; Mitogen-Activated Protein Kinase Kinases - metabolism; Neural Crest - metabolism; Neural Crest - pathology; Phenotype; Ribonuclease III - deficiency; Ribonuclease III - genetics; Severity of Illness Index; Syndrome; Traumas. Diseases due to physical agents; Human; microRNAs; Connective tissue disease; Skin disease; Dicer; Cardiovascular disease; vascular biology; CREST syndrome; Vascular disease; neural crest cells; cardiovascular development; Systemic disease; Atherosclerosis; Digestive diseases; Congenital cardiopathy
• ISSN: 1079-5642; 1524-4636; 1524-4636
• DOI: 10.1161/ATVBAHA.110.213306

OBJECTIVE—Congenital heart defects represent the most common human birth defects. Even though the genetic cause of these syndromes has been linked to candidate genes, the underlying molecular mechanisms are still largely unknown. Disturbance of neural crest cell (NCC) migration into the derivatives of the pharyngeal arches and pouches can account for many of the developmental defects. The goal of this study was to investigate the function of microRNA (miRNA) in NCCs and the cardiovascular system. METHODS AND RESULTS—We deleted Dicer from the NCC lineage and showed that Dicer conditional mutants exhibit severe defects in multiple craniofacial and cardiovascular structures, many of which are observed in human neuro-craniofacial-cardiac syndrome patients. We found that cranial NCCs require Dicer for their survival and that deletion of Dicer led to massive cell death and complete loss of NCC-derived craniofacial structures. In contrast, Dicer and miRNAs were not essential for the survival of cardiac NCCs. However, the migration and patterning of these cells were impaired in Dicer knockout mice, resulting in a spectrum of cardiovascular abnormalities, including type B interrupted aortic arch, double-outlet right ventricle, and ventricular septal defect. We showed that Dicer loss of function was, at least in part, mediated by miRNA-21 (miR-21) and miRNA-181a (miR-181a), which in turn repressed the protein level of Sprouty 2, an inhibitor of Erk1/2 signaling. CONCLUSION—Our results uncovered a central role for Dicer and miRNAs in NCC survival, migration, and patterning in craniofacial and cardiovascular development which, when mutated, lead to congenital neuro-craniofacial-cardiac defects.