title: Loss of microRNAs in neural crest leads to cardiovascular syndromes resembling human congenital heart defects.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Cell and Developmental Biology, McAllister Heart Institute, School of Medicine, University of North Carolina, Chapel Hill, USA.
authors.forename: Zhan-Peng
authors.initials: ZP
authors.lastname: Huang
authors.forename: Jian-Fu
authors.initials: JF
authors.lastname: Chen
authors.forename: Jenna N
authors.initials: JN
authors.lastname: Regan
authors.forename: Colin T
authors.initials: CT
authors.lastname: Maguire
authors.forename: Ru-Hang
authors.initials: RH
authors.lastname: Tang
authors.forename: Xiu Rong
authors.initials: XR
authors.lastname: Dong
authors.forename: Mark W
authors.initials: MW
authors.lastname: Majesky
authors.forename: Da-Zhi
authors.initials: DZ
authors.lastname: Wang
mesh_terms: D000015:Abnormalities, Multiple / Q000196:embryology / Q000235:genetics* / Q000473:pathology; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D016923:Cell Death; D002454:Cell Differentiation; D002465:Cell Movement; D002470:Cell Survival; D019465:Craniofacial Abnormalities / Q000196:embryology / Q000235:genetics* / Q000473:pathology; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D006330:Heart Defects, Congenital / Q000196:embryology / Q000235:genetics* / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009432:Neural Crest / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases; D043244:Ribonuclease III / Q000172:deficiency / Q000235:genetics*; D012720:Severity of Illness Index; D013577:Syndrome
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; C531950:MIRN21 microRNA, mouse; D008565:Membrane Proteins; D035683:MicroRNAs; C529100:mirn181 microRNA, mouse; D017346:Protein Serine-Threonine Kinases; C118389:Spry2 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D043244:Ribonuclease III