Transgenic mouse embryos lacking Notch receptors or downstream signaling components have congenital heart defects, including hypoplastic ventricular wall, ventricular septal and cushion malformations. The extent to which these defects reflect a requirement for Notch signaling in myocardial or other cells affected by the systemic knockouts has not been investigated. Additionally, the role of Notch in maintaining integrity and function of any adult tissue, including the heart, is largely uncharacterized. Thus, the proposed experiments use a combination of cell culture and transgenic mouse models to probe the role of Notch in fetal myocardial development and in maintaining adult myocardial structure and function.
Aim 1 is to evaluate the link between Notch activation and cell cycle control of immature cardiomyocytes (Aim 1). Evidence is presented that Notch extends the replicative period of ESC- derived and neonatal cardiomyocytes in vitro and the proposed studies will determine the point of cell cycle control and reversibility of the effect.
Aims 2 and 3 use conditional transgenic Cre-LoxP technology to identify the tissue of action, timing, and Notch isoform requirements for proliferation, lineage selection and morphogenesis of fetal heart development. Preliminary characterization of a conditional myocardial knockout (KO) of the Notch transcriptional mediator CSL/RBPJ/Su(H) revealed defects that, combined with expression data, indicate that Notch2 activity is essential for ventricular myocardial proliferation and morphogenesis. Lastly, Aim 4 is to develop transgenic models of adult loss of Notch function in the heart and test involvement during normal maturation and aging and following myocardial damage and hemodynamic overload. Our data indicate that late gestation to adult conditional myocardial KO of CSL causes ventricular remodeling by 3 months of age. These studies should extend knowledge of how this important developmental signaling pathway influences congenital and adult heart disease and specifically tests how it might be manipulated to control stem cell cardiogenesis for therapeutic applications.
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