Graduate Thesis Or Dissertation
 

Gene networks during cardiogenesis and skeletal myogenesis

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https://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/2r36v249w

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  • Organismal development requires a precisely orchestrated transcriptional program to correctly deploy genetic information into the genome. This process requires sophisticated gene regulatory networks at multiple spatial and temporal levels from early embryonic development to adult physiological conditions. Molecular differences that define cell types are set up during the pattern formation phase of development. Selective gene expression provides molecular markers such as sequence specific DNA-binding transcription factors (SSTFs) to define cell types. Homeodomain transcription factors are essential for embryonic pattern formation and cell specification and therefore can affect several mechanistically distinct aspects of organ development. The Pitx2 homeobox gene is expressed in the lateral plate mesoderm and it is involved in cardiac and skeletal muscle development. Mutations of Pitx2 are associated with the human Axenfeld-Rieger syndrome. Pitx2 null mice die at embryonic day 13.5 and exhibit un-septated atria and outflow tract that leads to deformed valves and arrythmias. Pitx2 promotes the proliferation of the branchial arch mesoderm-derived cells and their remodeling process, the epithelial-mesenchymal transition, to form the outflow tract cushions by influencing the expression of SSTFs in the cardiac mesoderm. Pitx2 is expressed in skeletal muscle cells from their time as progenitors until they form mature muscle groups. In Pitx2 null mutant mice the skeletal muscles have been specified, the muscles were formed but their higher order assembly was disrupted. Pitx2 was a key player of the embryonic muscle progenitors as they transition to the fetal state. Embryonic muscle progenitors were able to delaminate from the dermomyotome and migrate to the forelimb pre-patterned anlagen but were not fast to transition to the fetal state, as their G1 phase was arrested and their motility was disrupted. We have developed a Pitx2 conditional genetic system that eliminates the early cause of death and allows us to investigate the role Pitx2 at later stages. The molecular mechanisms of muscle regeneration in adults share many characteristics with the myogenic programs that generate skeletal muscle during development. These studies will enhance the molecular understanding of myogenic development and generate muscle-impaired mouse lines for drug and regeneration studies.
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