| Loss of microRNAs in neural crest leads to cardiovascular syndromes resembling human congenital heart defects. | |
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MedLine Citation:
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PMID: 20884876 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. 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. |
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Authors:
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Zhan-Peng Huang; Jian-Fu Chen; Jenna N Regan; Colin T Maguire; Ru-Hang Tang; Xiu Rong Dong; Mark W Majesky; Da-Zhi Wang |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-09-30 |
Journal Detail:
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Title: Arteriosclerosis, thrombosis, and vascular biology Volume: 30 ISSN: 1524-4636 ISO Abbreviation: Arterioscler. Thromb. Vasc. Biol. Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-11-18 Completed Date: 2010-12-21 Revised Date: 2011-12-21 |
Medline Journal Info:
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Nlm Unique ID: 9505803 Medline TA: Arterioscler Thromb Vasc Biol Country: United States |
Other Details:
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Languages: eng Pagination: 2575-86 Citation Subset: IM |
Affiliation:
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Department of Cell and Developmental Biology, McAllister Heart Institute, School of Medicine, University of North Carolina, Chapel Hill, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Abnormalities, Multiple
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embryology,
genetics*,
pathology Animals Cell Death Cell Differentiation Cell Movement Cell Survival Craniofacial Abnormalities / embryology, genetics*, pathology Embryo, Mammalian / abnormalities, metabolism Extracellular Signal-Regulated MAP Kinases / metabolism Gene Expression Regulation, Developmental* Genotype Heart Defects, Congenital / embryology, genetics*, pathology Humans Membrane Proteins / metabolism Mice Mice, Knockout MicroRNAs / metabolism* Mitogen-Activated Protein Kinase Kinases / metabolism Neural Crest / metabolism*, pathology Phenotype Ribonuclease III / deficiency, genetics* Severity of Illness Index Syndrome |
| Grant Support | |
ID/Acronym/Agency:
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R01 HL085635-04/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/MIRN21 microRNA, mouse; 0/Membrane Proteins; 0/MicroRNAs; 0/Spry2 protein, mouse; 0/mirn181 microRNA, mouse; EC 2.7.11.24/Extracellular Signal-Regulated MAP Kinases; EC 2.7.12.2/Mitogen-Activated Protein Kinase Kinases; EC 3.1.26.3/Ribonuclease III |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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