The mechanisms which promote cardiomyocyte proliferation during fetal life, and which fail to induce proliferation during postnatal life, are only poorly understood. My lab has studied cardiac development in mouse embryos lacking the retinoic acid receptor RXRa, in which compact zone formation in the ventricular chamber fails to initiate, resulting in a hypoplastic chamber that is incompatible with fetal viability. We have previously described this phenotype and shown that the initial response to retinoic acid during ventricular development does not occur in the myocardium, but rather occurs in a distinct cell lineage which then secondarily supports myocardial proliferation and subsequent ventricular chamber morphogenesis. Model: Based on new data presented in this application, I propose that retinoic acid signaling is initially transduced by RXRa in the epicardium, thereby inducing expression of one or more secreted growth factors which are trophic for the myocardium. Myocardium in older embryos and in postnatal animals is refractory to stimulation by these factors. To address this model, I propose the following Specific Aims: Specific Aim 1: To define the role of RXRa in the epicardium. Tissue-specific inactivation and transgenic manipulation in mouse embryos, and viral infection in chick embryos, are proposed to demonstrate that RXRa function occurs in the epicardium. Specific Aim 2: To identify the factor(s) secreted by epicardial cells in response to retinoic acid that are trophic for the myocardium. Biochemical purification plus gene-based discovery approaches are proposed to identify the factors secreted by epicardial cells in a retinoic acid- and RXRa-dependent manner. Specific Aim 3: To define the critical components of the myocardial response to epicardial cell secreted trophic factor(s). I propose to identify the signal transduction elements in fetal cardiocytes which mediate the response to trophic stimulation, as well as changes which account for the lack of response in postnatal myocardium.
NIH ExPorter
NIH ExPorter