Co-regulatory Model of Smooth Muscle Myogenesis

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DESCRIPTION (provided by applicant): Smooth muscle is critical to the normal development and function of the gastrointestinal (GI) tract, while the dysregulation of smooth muscle differentiation results in GI pathologies ranging from birth defects to inflammatory diseases to smooth muscle tumors. A key component in either the development or progression of each of these diseases is an alteration in GI smooth muscle cell (SMC) phenotype. These phenotypic changes consistently reflect a shift from the mature smooth muscle myocyte towards the less differentiated smooth muscle myoblast. The fact that similar changes in SMC phenotype are observed independent of disease etiology suggests that these pathologies converge upon a common cellular pathway that controls or maintains GISMC differentiation. The long-term objectives of this proposal are to gain a better understanding of the critical events modulating GISMC differentiation in both normal and pathogenic GISMCs. Recent studies in our lab indicate that GI smooth muscle differentiation requires the coordinate activation of a distinct subset of transcription factors including serum response factor (SRF), Nkx2-3, and an unidentified AT-rich binding factor. Activity of this regulatory complex centers upon SRF binding to a core CArG-box domain, and appears both developmental and tissue-specific. In addition, our studies indicate that altered patterns of transcription factor utilization are associated with smooth muscle pathogenesis. Clarifying the key role that SRF plays in modulating smooth muscle differentiation is therefore critical to gaining a better understanding of GI smooth muscle development and pathogenesis. To this end, we plan to functionally assess the role of SRF in modulating GI smooth muscle differentiation using morpholino-based antisense technology and transgenic mice. In addition, we will identify and characterize a unique, smooth muscle myoblast-specific AT-rich binding factor found associated with the SRF-Nkx2-3 transcriptional complex in an effort to determine its role in regulating gene expression in this important cellular phenotype.