Mechanistic Analysis of SRF and the Myocardin Family of Coactivators During Muscle Development

dc.contributor.advisorOlson, Eric N.en
dc.creatorLi, Shijieen
dc.description.abstractThe precise mechanism of how specification and differentiation of different muscle types are controlled by a large number of transcription factors has been a long-standing question in developmental biology. Using animal models with tissue-specific deletions of various transcription factors, coupled with biochemical studies, the molecular mechanisms regulating muscle development and growth are being elucidated. Serum response factor (SRF), a muscle-enriched transcription factor, activates the expression of numerous muscle genes by recruiting a variety of partner proteins. The function of SRF in each muscle type in vivo is clouded by the fact that SRF mutant mice die before gastrulation without the formation of mesoderm. Generating a tissue-specific deletion of the SRF gene, I found that SRF is required for skeletal muscle growth and maturation. Myocardin was identified as a cardiac and smooth muscle-specific transcriptional coactivator of SRF. Mice lacking myocardin die during early embryogenesis due to cardiovascular defects, which are caused by the failure of vascular smooth muscle to differentiate. Together with the data that overexpression of myocardin in non-muscle cells can activate the smooth muscle gene program, we demonstrate that myocardin is both required and sufficient for smooth muscle differentiation. Two Myocardin Related Transcription Factors, referred to as MRTF-A and B, which also interact with SRF and stimulate its transcriptional activity, are expressed in numerous embryonic and adult tissues, implying their potential to modulate SRF target genes in a wide range of tissues. Consistent with the role of SRF during skeletal muscle development, a dominant-negative form of MRTF-A interferes with skeletal muscle development in transgenic mice. To further elucidate MRTF-A's function, I generated MTTF-A mutant mice by gene homologous recombination. Female MRTF-A mutant mice fail to nurture their offspring due to mammary defects. While milk is produced at a normal level, mammary myoepithelial cells, which are similar to smooth muscle cells and required for milk ejection, fail to differentiate and undergo programmed cell death during lactation. Taken together, these data indicated that SRF regulates specification or maturation of different muscle types by interacting with various members of the myocardin family of coactivators.en
dc.format.digitalOriginborn digitalen
dc.subjectTranscription Factorsen
dc.subjectSerum Response Factoren
dc.titleMechanistic Analysis of SRF and the Myocardin Family of Coactivators During Muscle Developmenten
dc.type.materialTexten School of Biomedical Sciencesen and Developmenten Southwestern Medical Centeren of Philosophyen


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