Jayne Wright

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. In order for the heart to function properly it must have its own blood supply. Blood is delivered to the heart through a system of vessels called the coronary vasculature. During development, some of the cells that form the coronary vessels originate from the epicardium, the outer layer of the heart. These epicardial-derived cells migrate into the cardiac tissue where they contribute to the formation of the coronary vascular network. We have found that a mouse mutant containing a mutation in the gene Myh10, which encodes the cytoskeletal protein non-muscle myosin IIB, fails to form the coronary vasculature. Our work reveals defects in the epicardium, which contribute to the lack of coronary vessel development in this mutant. Surprisingly, we discovered that whilst the mutant epicardial cells are capable of movement when extracted from the embryo, these cells fail to mobilise into a vascular network in the context of the developing embryonic heart. We propose that this migration failure is due to abnormalities in the extracellular environment in the mutant heart. This work highlights the importance of the Myh10 gene in the critical developmental process of coronary vessel formation.