Loss of MicroRNAs in neural crest leads to cardiovascular syndromes resembling human congenital heart defects

Zhan Peng Huang, Jian Fu Chen, Jenna Regan, Colin T. Maguire, Ru Hang Tang, Xiu Rong Dong, Mark W. Majesky, Da Zhi Wang

Research output: Contribution to journalArticle

62 Citations (Scopus)

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. 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.

Original languageEnglish (US)
Pages (from-to)2575-2586
Number of pages12
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume30
Issue number12
DOIs
StatePublished - Dec 2010
Externally publishedYes

Fingerprint

Congenital Heart Defects
Neural Crest
MicroRNAs
Cell Movement
Double Outlet Right Ventricle
Cardiovascular Abnormalities
Branchial Region
Survival
Ventricular Heart Septal Defects
Cell Lineage
Cardiovascular System
Thoracic Aorta
Knockout Mice
Cell Survival
Cell Death
Genes
Proteins

Keywords

  • cardiovascular development
  • Dicer
  • microRNAs
  • neural crest cells
  • vascular biology

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Loss of MicroRNAs in neural crest leads to cardiovascular syndromes resembling human congenital heart defects. / Huang, Zhan Peng; Chen, Jian Fu; Regan, Jenna; Maguire, Colin T.; Tang, Ru Hang; Rong Dong, Xiu; Majesky, Mark W.; Wang, Da Zhi.

In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 30, No. 12, 12.2010, p. 2575-2586.

Research output: Contribution to journalArticle

Huang, Zhan Peng ; Chen, Jian Fu ; Regan, Jenna ; Maguire, Colin T. ; Tang, Ru Hang ; Rong Dong, Xiu ; Majesky, Mark W. ; Wang, Da Zhi. / Loss of MicroRNAs in neural crest leads to cardiovascular syndromes resembling human congenital heart defects. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 2010 ; Vol. 30, No. 12. pp. 2575-2586.
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