The research plan describes a somatic cell genetics approach to identify factors collaborating with MyOD in skeletal muscle-specific transcriptional activation. MyoD and related basic helix-loop-helix proteins function as master switches of skeletal muscle differentiation. Specific gaps in knowledge remain pertaining to how MyoD is activated at the appropriate point in development and what factors upon which it is dependent to function. The broad long term objective of this work is to better understand the transcriptional circuitry leading to skeletal muscle development.
The specific aims of this proposal are these: 1. Develop a somatic cell genetics approach in tissue culture cells to identify genes controlling muscle development. 2. Identify factors acting parallel or downstream from MyoD in muscle differentiation. 3. Identify factors leading to transcriptional activation of MyoD 4. Pursue preliminary studies tentatively identifying a single factor promoting transcriptional activation of MyOD and cell cycle withdrawal. This objective has relevance to the understanding of human disease, including muscular dystrophy and those birth defects arising from disturbances in tissue differentiation.
| Coonrod, A; Li, F Q; Horwitz, M (1997) On the mechanism of DNA transfection: efficient gene transfer without viruses. Gene Ther 4:1313-21 |
| Horwitz, M (1996) Hypermethylated myoblasts specifically deficient in MyoD autoactivation as a consequence of instability of MyoD. Exp Cell Res 226:170-82 |
| Li, F Q; Coonrod, A; Horwitz, M (1996) Preferential MyoD homodimer formation demonstrated by a general method of dominant negative mutation employing fusion with a lysosomal protease. J Cell Biol 135:1043-57 |
| Gogos, J A; Thompson, R; Lowry, W et al. (1996) Gene trapping in differentiating cell lines: regulation of the lysosomal protease cathepsin B in skeletal myoblast growth and fusion. J Cell Biol 134:837-47 |
