| The myocyte enhancer factor 2 (MEF2) family of MADS-box containing transcription factors play important roles in skeletal muscle differentiation, immediate early gene expression, neuronal survival, calcium signaling, metabolism, and apoptosis. Previous gene knockout studies demonstrated a role for mef2c in early heart development as mice lacking mef2c die as embryos at E9.5 with hearts consisting of a hypoplastic embryonic ventricle and an enlarged sinoatria. The present study was undertaken to better understand the role of mef2c in heart development, specifically to address why its absence produced a smaller ventricle and if it might also function in the later stages of heart development such as cardiac chamber formation.; Morphological and histological analyses of wildtype and mef2c -/- embryos at various stages of cardiac development indicated that differences appeared very early in heart development; cardiac crescents from mef2c-/- embryos were unable to expand to form normal linear heart tubes. Mef2c-/- cardiomyocytes were rounded and disorganized. TUNEL assay and immunohistochemical staining for phospho-histone H3, a mitotic marker, showed that proliferation but not apoptosis was affected. Collectively, these observations suggested that the differences between wildtype and mef2c-/- embryos resulted from a failure of cardiomyocytes to differentiate and proliferate; thus, preventing cardiomyocytes from contributing to the formation of the embryonic ventricle. Supporting this notion, the expression of ventricle- and atrial-specific markers as assayed by whole mount in situ hybridization and reporter transgene studies demonstrated that a displacement of cardiomyocytes from the ventricular to the atrial lineage had occurred in mef2c-/- hearts. Thus, the smaller embryonic ventricle observed in mef2c-/- hearts resulted from the redistribution of presumptive ventricular precursors to the sinoatria. Remarkably, MEF2C did not appear to be necessary for the later stages of heart development, such as cardiac chamber formation, as myocardial-specific removal of the mef2cloxP/loxP allele in mice produced offspring, which were viable and whose hearts developed normally. Thus, the findings of the present study demonstrated a novel role for MEF2C in the differentiation of ventricular precursors cells and the normal allocation of cells between the ventricular and atrial regions during formation of the embryonic ventricle. |
