Roles of Myocardin-Related Transcription Factors in Muscle and Brain

Abstract

Partnerships between DNA binding transcription factors and transcriptional cofactors govern gene transcription in various developmental and tissue contexts, particularly during cardiovascular and neuronal development. This dissertation aims at studying the in vivo relevance of the partnership between Serum response Factor (SRF) and its Myocardin Related Transcription Factor (MRTF) coactivators during development. I present here my studies on the functions of MRTFs during brain and muscle development. First, I show that MRTF-A and -B redundantly control neuronal migration and neurite outgrowth during brain development. Conditional deletion of these genes in the mouse brain disrupts the formation of multiple brain structures, reflecting a failure in neuronal actin polymerization and cytoskeletal assembly. I also describe a previously unrecognized role for the MRTF/SRF pathway in the regulation of the Pctaire-1/Cdk5 kinase cascade to govern actin dynamics. I conclude that MRTFs function as essential coregulators of SRF to control actin dynamics during neuronal development via the Cdk5/Pctaire-1 kinase cascade. I also explore the role of MRTF-A and -B in cardiac development and function. Ablation of these MRTF genes in the embryonic heart causes` a range of cardiac defects, reflecting the sensitivity of cardiac function to MRTF gene dosage. Moreover, I show that the gene encoding Pctaire-1 kinase, whose functions in the heart are unknown, is also a target of MRTF/SRF signaling and a regulator of sarcomere assembly in the heart. Furthermore, by creating mice lacking the Myocardin related factor MASTR, I explore the in vivo developmental functions of MASTR. Germline deletion of MASTR alone does not cause any obvious defects in mice. However, deletion of MASTR in an MRTF-A null background causes perinatal lethality, which appears to be due to defective skeletal muscle growth and development. Thus, the results of my thesis research demonstrate that MRTFs are essential regulators of multiple developmental processes in brain, heart, and skeletal muscle. At the cellular level, MRTFs are essential regulators of the actin cytoskeleton. Disruption of MRTF functions, whether in neurons or in muscle cells, causes major cytoskeletal defects that impair brain and muscle development and function. [Keywords: MRTF; skeletal muscle; cardiac development; actin dynamics; neurite outgrowth; neuronal migration; MASTR; Pedtaire-1; myocardin; sarcomere assembly]