This proposal involves the use of transgenic mice to examine the role of Pax3 in somite and muscle development. This project will determine the DNA regulatory regions responsible for Pax3 expression in myogenic pecursors, and will use these regulatory regions in a transgenic approach to determine normal Pax3 function during formation of the limb musculature.
The specific aims are: 1. To clone the regulatory elements responsible for Pax3 expression in the somite and myogenic precursors. 2. To rescue congenital defects in muscle formation in Pax3 deficient mice. 3. To determine downstream muscle specific targets of Pax3. The regulatory regions required for normal Pax3 expression in the somite and migratory myoblasts will be isolated. Transgenic mice will be generated that express Pax3 under the control of this muscle specific promoter, and rescue of the Pax3 mouse mutant splotch will be attempted by breeding transgenic animals onto a splotch background. Novel downstream targets of Pax3 will be isolated by a PCR based representational difference analysis protocol. These experiments will provide important insight into the role of PAX3 in the formation of the limb musculatore, and this infomation will be broadly important to the study of myogenesis. Mutations in the human homologue of Pax3 cause Waardenburg syndrome., a syndrome usually characterized by sensory deafness and pigmentary disorders. Individuals with type III Waardenburg syndrome have limb muscle hypoplasia. The results of this study will also have broad import to the study of myogenesis and will therefore have relevance to the large number of both adult onset and congential diseases of the skeletal muscle.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Postdoctoral Individual National Research Service Award (F32)
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Cell Development and Function Integrated Review Group (CDF)
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Lymn, Richard W
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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