The morphological events forming the body's musculature are sensitive to genetic and environmental perturbations with high incidence of congenital myopathies, muscular dystrophies and degenerations. Thus, it is of a great need to better understand the molecular mechanisms regulating vertebrate muscle development and regeneration. Recent advances in human and mouse molecular genetics has illuminated key events of early muscle patterning and morphogenesis which lead to stem cell therapies for muscle fiber repair. Early developmental events share the same molecular networks with regenerated skeletal muscle. Our long term objective of these studies is to define the molecular pathways involved during muscle development, maturation and repair. The paired-like homeodomain transcription factor Pitx2, known as the gene that is mutated in the autosomal dominant Rieger syndrome, is a critical player in the formation of the heart and other organs. Pitx2 gene deleted mice exhibit cardiac malformations, skeletal muscle defects, and right pulmonary and atrial isomerism that are indicative of the loss of left-sided identity. Pitx2 is rapidly induced by the Wnt/B-catenin pathway, and is required for effective myoblast proliferation by directly activating growth control genes like cyclins. Pitx2 serves as a competence factor required for the temporally ordered and growth-factor dependent recruitment of a series of specific co-activator complexes. We hypothesize that Pitx2 regulates the fate and specification of muscle lineages as they migrate to the different parts of the body. Our goal is to identify the molecular mechanisms that specify how muscle cell lineages form the body's musculature.
In Aim 1 we will define the function of Pitx2 in the skeletal muscle precursor lineage using indelibly labeled mouse cell lineages.
In Aim 2 we will determine the function of Pitx2 in the committed/differentiated muscle lineages by ablated Pitx2 in differentiated muscle cells. In both Aims target genes will be identified my microarray analyses. The successful completion of these studies will provide novel insights as to how cells from different origins are interacting to form skeletal muscle groups and how genetic factors are contributing to this developmental process. Technology and mouse model systems generated from this research will help to elucidate the molecular basis on etiology and repair of muscular degenerative diseases. ? ? ? ?
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