The KLF Family of Transcriptional Regulators in Cardiomyocyte Proliferation and Differentiation

Unlike other organs, the adult heart has limited regenerative potential owing to the inability of postnatal cardiomyocytes to undergo proliferative growth. As a result, ischemic heart disease continues to be a major cause of morbidity and mortality worldwide. Elucidating the molecular pathways of cardiomyocyte differentiation and proliferation holds great promise for human health. In a recent paper we employed a multidisciplinary approach to identify a novel pathway required for cardiomyocyte growth and differentiation. Starting with the dissection of a new regulatory sequence required for cardiac specific expression, we identified the cognate DNA binding protein as KLF13, a tissue-restricted member of the newly identified KLF family of zinc-finger proteins. We took advantage of the ease in manipulating Xenopus embryos to genetically alter KLF13 levels thus demonstrating a requirement for KLF13 in cardiac progenitor cell proliferation and heart morphogenesis. Furthermore, we combined biochemical approaches with genetic manipulations in Xenopus to show that KLF13 is a GATA4 interacting protein and a genetic modifier of GATA4 function. Cyclin D1 was identified as a direct transcriptional target for KLF13 that may account for the proliferation defects observed in embryos with downregulated KLF13 levels. Thus, tissue-specific regulators of the cell cycle may be potential congenital heart disease causing genes in humans.