| Cardiomyocyte differentiation is a complex coordination of cellular and molecular transformations which allows a mature cardiomyocyte to perform a specialized function within the chambered heart. Both intrinsic and extrinsic cues mediate the transition of a cardiomyocyte progenitor into a differentiated cardiomyocyte. However, very little is known about the molecular pathways that govern this differentiation process. In this thesis, we explore the regulation of differentiation in cardiomyocyte progenitors.;We identified a novel para-zinc finger transcription factor, CASTOR (CST), which is expressed within the cardiomyocyte progenitors immediately prior to the onset of cardiac differentiation. We show that CST is required for the differentiation of the ventral midline cardiomyocyte progenitor population and to regulate the proliferation of the differentiated lateral cardiomyocytes. In the absence of CST, this ventral midline cardiomyocyte population remains in the progenitor state. Fate mapping of the ventral midline cardiomyocyte progenitors reveals that they ultimately contribute to the outer curvature of the future ventricle. However, the CST-depleted ventral midline cardiomyocyte progenitors overproliferate and remain as a coherent population of nonintegrated cells in the outer wall of the myocardium.;To begin to decipher how CST regulates cardiomyocyte differentiation, we performed a bacterial one-hybrid assay to determine that CST binds to a ten basepair DNA binding sequence CTAGTGGTGG. In addition, we used a cloning chromatin immunoprecipitation (ChIP) screen to identify direct transcriptional target genes of CST. We further show that CST may regulate the transcription of genes associated with cell growth control, cell migration and adhesion, Wnt signaling and myocardium patterning. This work provides insight into how CST may influence cardiomyocyte differentiation. |
