REGULATION OF SMOOTH MUSCLE DIFFERENTIATION

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Smooth muscle cells are essential for the function of the circulatory, urogenital, respiratory, and digestive systems, yet little is understood about how the differentiation of these contractile cells is regulated. Our long-term goal is to gain insight into the molecular mechanisms underlying smooth muscle development. We have identified and characterized two highly conserved proteins, cysteine-rich protein 1 (CRP1) and cysteine-rich protein 2 (CRP2), that are prominently expressed in smooth muscle derivatives. CRPs are comprised more or less exclusively of two LIM domains, double zinc finger structures that are found in many proteins that play key roles in cell differentiation during development. Recently, a third member of the CRP family that is expressed in striated muscle has been demonstrated to be essential for the differentiation of cardiac and skeletal muscle cells in vivo. We postulate that CRP1 and CRP2 play critical roles in the differentiation of vascular and visceral smooth muscle. The roles of CRP1 and CRP2 in smooth muscle myogenesis will be explored using the mouse as a model system. The spatial and temporal patterns of expression of the genes encoding CRP1 and CRP2 will be defined at high resolution in embryos and adults by in situ hybridization and immunocytochemical methods. Mice that lack CRP1 or CRP2 expression will be generated by targeted gene disruption methods and the phenotypic consequences for smooth muscle structure and function will be evaluated. In order to define the molecular roles of CRP1 and CRP2 within cells, the subcellular distributions and binding partner repertoires of the proteins will be established. These studies are expected to provide mechanistic insight into a pathway required for the generation of smooth muscle. Smooth muscle cells are unusual in their phenotypic plasticity. In response to physiological stimuli, smooth muscle cells can shift from a differentiated to a proliferative state. Hyperplasia of smooth muscle cells in the vasculature is a central contributor to the development of atherosclerosis and to restenosis after angioplasty. Understanding the molecular mechanisms underlying smooth muscle differentiation is an essential prerequisite to the development of rational therapeutic approaches to control the behavior of smooth muscle cells in vivo.