Role of Pitx2 in regulation of cardiac remodelling Public Deposited

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/8k71nk267

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  • Background: Heart morphogenesis involves chamber formation followed by septation. Septation is the remodeling of the heart from a single channel peristaltic pump to a two channel pump with one-way valves. Several transcription factors have been implicated in the development of congenital cardiac defects. The paired-like homeodomain transcription factor Pitx2 has essential roles in the development of the eye, tooth, pituitary, skeletal muscle, and heart in mammals. Pitx2 mutant mice characterized by septational defects in the atria, ventricles and outflow tract during cardiac development. Pitx2 acts downstream of the Wnt/Dvl/ß-catenin pathway and regulates the expression of cell cycle control genes during cardiac development. Results: Cells from the branchial arch mesoderm (Isl1+ and Mef2c+) and cardiac neural crest (Wnt1+ and AP2+) migrate and contribute to the outflow tract and right ventricle. Lineage tracer analysis using specific Cre mouse lines for branchial arch mesoderm-derived cells (Mef2cCre) and neural crest cells (AP2Cre, Wnt1Cre) indicated that Pitx2 was expressed in subpopulations of both cell lineages. Cardiac chambers were not properly formed in the Pitx2 mutant mice as cells of the branchial arch mesoderm (Isl1+ and Mef2c+) and neural crest lineages failed to migrate and populate the structures of the outflow tract and right ventricle. Septation along the outflow tract and right ventricle did not progress to form the atrioventricular cushions and interventricular septum as the hypocellular structures did not follow apoptosis and entered remodeling. Conclusions: Pitx2 contributes to the formation of the cardiac septae by providing the proper environmental cues to branchial arch mesoderm and neural crest cells to migrate in the developing heart and enter the remodeling program during cardiac development.
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