COREGULATORY MODEL OF SMOOTH MUSCLE MYOGENESIS

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Mature gastrointestinal (GI) smooth muscle cells (SMCs) possess a high degree of developmental plasticity retaining the ability to interconvert between proliferative and differentiated states in response to external stimuli. Dysregulation of GI SMC differentiation is associated with a variety of GI disorders including Hirschsprung's disease, Crohn's disease, ulcerative colitis, motility disorders, and GI smooth muscle tumors. The goal of this proposal is to gain a better understanding of the molecular mechanisms controlling GI smooth muscle development. Our hypothesis is that GI smooth muscle myogenesis is controlled by the synergistic expression of transcription factors that are common to all muscle lineages, as well as those that are smooth muscle specific. This hypothesis is supported by recent data from our lab identifying a key regulatory complex within the gamma-smooth muscle isoactin gene promoter. Interconversion between proliferative and differentiated GI SMC phenotypes involves differential binding of serum response factor (SRF), distinct isotypes of MEF2, and additional unidentified transcription factors to this critical regulatory complex. Utilization of these same transcription factors by this complex is altered in G1 smooth muscle tumors and ulcerative colitis suggesting that SRF and MEF2 may play a role in GI smooth muscle pathogenesis. We plan to identify the key transcription factors involved in GI smooth muscle myogenesis by elucidating the factors controlling gamma-smooth muscle isoactin gene expression in primary cultures of GI SMCs. We will use a unique, mass-arrayed screening technique to isolate and identify novel GI smooth muscle-specific transcription factors. Cultured GI SMCs will be used to assess the functional role that SRF, MEF2, and novel transcription factors play in modulating GI SMC differentiation. Identifying the key transcription factors involved in GI smooth muscle myogenesis, and determining how they interact to modulate GI SMC phenotype is critical to gaining a better understanding of GI smooth muscle pathogenesis in a variety of GI diseases.