Gene regulatory networks during muscle development Public Deposited

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/tt44pp931

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  • Congenital myopathies are caused by heritable mutations in particular genes. Genes mutated in congenital muscular dystrophies often encode cytoskeletal proteins, which contribute to the shape and movement of cells. We would like to know how such molecular defects lead to the muscle weakness in patients. It is therefore important to understand the molecular and cellular mechanisms by which muscle cells form, grow, and assemble into functional muscles. The bicoid–related homeobox gene Pitx2 is expressed in the developing embryo, regulates organogenesis, and is associated with several human congenital diseases. Pitx2 specifies and maintains several cell populations as they form specific organs by acting as a node within individual distinct network kernels. We hypothesize that lack of functional Pitx2 results in major changes in the gene regulatory networks involved in skeletal myogenesis. Pitx2 is expressed in all muscles during development, and thus the Pitx2-null mouse is an informative model to study myogenesis. Absence of Pitx2 results in an open abdominal wall followed by absence of abdominal musculature. Gene expression microarrays of E10.5 wild type and mutant Pitx2 mouse body wall have shown that Pitx2 can act as an inhibitor of protein transport and cell apoptosis. Loss of Pitx2 results in the altered specification of the abdominal Hox network that is involved in patterning, of which the Hox genes are normally occupied, positively regulated, and stabilized by Pitx2 function in the abdomen. The loss of proper Hox patterning results in the loss of the somatopleure and thus loss of somite-derived musculature. In the somites, the initiation and maintenance of the myogenic program is independent of Pitx2 function, in lieu of Pitx2 occupancy on the myogenic regulatory factors (MRFs). Absence of functional Pitx2 in the limbs results in muscle malformation with defects in the higher order assembly, including adhesion molecules and cytoskeletal proteins. The chromatin state of normal and Pitx2 mutant limbs as a whole at E12.5 indicated no significant difference between genes involved in transcription, transcriptional regulation, or organ development. However, genes involved in myogenic networks are bivalently marked and thus likely being poised for activation or repression. Future work will focus on identifying differences in the chromatin state of myogenic cells as they progress to make a functional muscle.
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