Multifunctional Regulators of Cardiac Disease and Development

Embryogenesis requires delicate regulatory mechanisms. A single cell embryo divides into millions of daughter cells to form an organism comprised of various organs with different shapes and function. Organogenesis is mainly controlled by genes that are expressed in a tissue-specific manner. Thus, regulation of gene expression is a critical step in development. In this thesis, I present my findings on two cardiac transcription factors MEF2 and Yap that play multiple roles in development. First, I show a novel function of myocyte enhancer factor 2 (MEF2) transcription factors in development of endochondral bone. MEF2 proteins are widely known as essential regulators of development of various tissues such as striated muscle and brain. Based on expression patterns of Mef2 genes and skeletal defects present in Mef2c +/-; Mef2d +/- mice, I hypothesized that MEF2is an important regulator of skeletogenesis and generated mice lacking MEF2C and MEF2D in chondrocytes using Mef2c and Mef2d conditional mutant alleles. From this study, I demonstrated that MEF2 proteins are also critical regulators of chondrocyte hypertrophy at least partly through their regulation of procollagen, type X, alpha 1 (Col10a1). I also explored another function of MEF2 protein, which is to mediate stress-dependent cardiac remodeling. Mef2d null mice show impaired response to cardiac remodeling stresses such as pressure overload and chronic Β- adrenergic stimulation; hypertrophy, chamber dilation, fibrosis, and fetal gene activation were blunted in the absence of MEF2D. Conversely, overexpression of MEF2D is sufficient to drive pathological remodeling of the heart. These findings reveal an important role of MEF2D in stress-dependent cardiac growth and reprogramming of gene expression in the adult heart. Finally, I demonstrate that yes-associated protein (Yap) serves as a critical regulator of cardiac function and angiogenesis by generating a Yap conditional mutant allele. Deletion of Yap in cardiomyoctes leads to lethal cardiomyopathy resulting from compromised cardiac angiogenesis and ischemia. I also identify Yap as a coactivator of GATA4, a trascription factor that functions as a regulator of angiogenesis in the heart. Moreover, my studies on deletion of Yap in other tissues suggest the possible role of Yap as a global angiogenic factor. Collectively, these studies show that key transcriptional regulators of cardiogenesis play a significant role not only in heart development, but also in development of other organs. These findings imply that combinatorial actions of transcriptional regulators in a tissue-specific manner are critical in embryogenesis.