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Myocardin: A Powerful SRF-Coactivator Required for Normal Smooth Muscle and Cardiac Ventricular Development

Hoofnagle, Mark Houston
Format
Thesis/Dissertation; Online
Author
Hoofnagle, Mark Houston
Advisor
Bender, Tim
Somlyo, Avril
McNamara,, Coleen
Owens, Gary
Abstract
Myocardin is a serum response factor (SRF) cofactor initially identified by in silico screening for transcription factors specific to the heart during development. It was soon implicated as a powerful activator of numerous smooth muscle cell (SMC) CArGdependent proteins as well, including smooth muscle alpha actin (SMA), smooth muscle myosin heavy chain (SMMHC), and SM22 in numerous in vitro systems of SMC. In this study, we confirmed and expanded upon the analysis of myocardin in the chimeric injection model. We discovered a cardiovascular phenotype in myocardin null ESC with failure of ESC-derived cells to contribute to the majority of the ventricular myocardium, lower contribution of myocardin null cells to vascular SMC as well as a failure of myocardin null cells to contribute to diverse visceral SMC types. Developmentaly the cardiac phenotype emerges between 12.5 and 14.5 dpc in chimeric embryos, although the few cells that ultimately populate the ventricular appear normal by ultrastructural analysis. Studies of in vitro cardiac gene expression in the EB model showed alterations in the expression of several cardiac sarcomeric genes (notably myosin light chain 2v (MLC2V), Cardiac -actin (CAA), and cardiac troponin T (cTnT)) but SMC genes were unchanged with the exception of SMMHC. Critically, the in vitro model also showed a delay in the formation of foci of cardiac contraction, although SMC contraction in cell lines purified from embryonic stem cells (ESC) was largely equivalent between wild type and null ESC-derived SMC. We hypothesize that myocardin is required for correct ii temporal expression of cardiac and SMC genes, and in its absence a critical delay in gene expression occurs preventing timely cardiac and visceral SMC contraction that is responsible for the observed phenotype. Based on these results we believe that, in the mouse, myocardin is required for normal cardiac development, and suggest that the conventional myocardin knockout mouse phenotype of absent SMC formation originally described by Olson may instead have been at least partially due to the absence of adequate cardiac contraction. Further, we believe that myocardin is a critical factor for visceral SMC development, and that careful study of myocardin's functions during embryonic development may elucidate the genetic mechanisms responsible for differences between vascular and visceral SMC. Note: Abstract extracted from PDF text
Language
English
Published
University of Virginia, Department of Physiology, PHD, 2007
Published Date
2007-01-01
Degree
PHD
Collection
Libra ETD Repository
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