Wnt and Notch Regulation of Cardiac and Vascular Smooth Muscle Gene Expression During Differentiation.

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During cardiovascular development, the heart and the great vessels that deliver blood to the body and lungs arise from at least three sources within the embryo. These include the first and second heart fields and a group of neural crest cells that migrate from the base of the skull to form the large vessels leaving the heart. Interestingly, the second heart field cells will ultimately become both heart muscle of the right ventricle and vascular smooth muscle cells of the great vessels. However, the mechanisms that determine this choice between heart and smooth muscle speciality remains unknown. Regulation of cell specialization, more generally, is regulated by secreted factors and cell-to-cell contact. The Wnt and Notch families of signaling molecules regulate cell specialization in this manner, and represent critical developmental cues that dictate organ formation in multiple biological systems. However, the role of these signaling pathways in cardiovascular development, as well as in the specialization of heart or vascular smooth muscle tissue is less understood. Interestingly, genetic inhibition of the myocyte enhancer factor 2C (MEF2C) gene in mice has uncovered a critical role for this transcription factor in cardiac second heart field and neural crest specialization. Therefore, utilizing techniques of cell and molecular biology, this research proposes to test the hypothesis that Wnt and Notch signaling pathways regulate cardiac and vascular smooth muscle specialization through modulation of MEF2C activity. Completion of this experimental objective will provide a new molecular insight into our understanding of this aspect of cardiovascular development, which could prove to be critical for future applied studies aimed at deciphering acquired and genetic defects affecting the heart.**