Non-muscle Myosin IIB (Myh10) Is Required for Epicardial Function and Coronary Vessel Formation During Mammalian Development

Liam A Ridge, Karen Mitchell, Ali Al-Anbaki, Wasay Mohiuddin Shaikh Qureshi, Louise A Stephen, Gennadiy Tenin, Yinhui Lu, Irina-Elena Lupu, Christopher Clowes, Abigail Robertson, Emma Barnes, Jayne A Wright, Bernard Keavney, Elisabeth Ehler, Simon C Lovell, Karl E Kadler, Kathryn E Hentges

Research output: Contribution to journalArticlepeer-review

Abstract

The coronary vasculature is an essential vessel network providing the blood supply to the heart. Disruptions in coronary blood flow contribute to cardiac disease, a major cause of premature death worldwide. The generation of treatments for cardiovascular disease will be aided by a deeper understanding of the developmental processes that underpin coronary vessel formation. From an ENU mutagenesis screen, we have isolated a mouse mutant displaying embryonic hydrocephalus and cardiac defects (EHC). Positional cloning and candidate gene analysis revealed that the EHC phenotype results from a point mutation in a splice donor site of the Myh10 gene, which encodes NMHC IIB. Complementation testing confirmed that the Myh10 mutation causes the EHC phenotype. Characterisation of the EHC cardiac defects revealed abnormalities in myocardial development, consistent with observations from previously generated NMHC IIB null mouse lines. Analysis of the EHC mutant hearts also identified defects in the formation of the coronary vasculature. We attribute the coronary vessel abnormalities to defective epicardial cell function, as the EHC epicardium displays an abnormal cell morphology, reduced capacity to undergo epithelial-mesenchymal transition (EMT), and impaired migration of epicardial-derived cells (EPDCs) into the myocardium. Our studies on the EHC mutant demonstrate a requirement for NMHC IIB in epicardial function and coronary vessel formation, highlighting the importance of this protein in cardiac development and ultimately, embryonic survival.
Original languageEnglish
Article numbere1007068
Pages (from-to)e1007068
JournalPL o S Genetics
Volume13
Issue number10
Early online date30 Oct 2017
DOIs
Publication statusPublished - 30 Oct 2017

Keywords

  • Animals
  • Cell Differentiation/genetics
  • Coronary Vessels/growth & development
  • Embryo, Mammalian
  • Embryonic Development/genetics
  • Epithelial-Mesenchymal Transition/genetics
  • Humans
  • Hydrocephalus/genetics
  • Mice
  • Mice, Knockout
  • Mutation
  • Myocardium/metabolism
  • Myosin Heavy Chains/genetics
  • Nonmuscle Myosin Type IIB/genetics
  • Pericardium/growth & development

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