During embryonic development, cells become committed to distinct cell lineages and differentiate to form the diverse types of cells that make up an animal. A functionally important example of cell commitment and specialization occurs during skeletal muscle formation. Muscle fibers first form from myoblasts in the somites, and primary (embryonic) and secondary (fetal) generations of skeletal muscle fibers subsequently form in the developing trunk and limbs. The initiation of somitic myogenesis appears to require interaction with the neural tube and expression of one or more of the four muscle regulatory factors (MRFs) - MyoD, myogenin, Myf-5, and MRF4. In particular, the formation of myoblasts requires either Myf-5 or MyoD, and the formation of muscle fibers requires myogenin in vivo. By birth, muscle fibers are innervated and have diversified into the different fiber types (e.g., fast and slow) which are necessary for proper muscle function. When this muscle cell specialization is abnormal, as in people with fiber type disproportion syndromes, muscle function is greatly impaired. Recently, we have found that somites are divided into multiple subdomains that can be identified because the myogenic cells in each domain express a distinct pattern of the four MRFs. This result raises the possibility that differential MRF expression underlies muscle cell specialization. The proposed experiments will answer questions about the MRF proteins and cellular mechanisms in myogenic cell specialization.
The specific aims are to (i) Determine how individual MRFs control spatial and temporal aspects of myogenesis by preparing and analyzing transgenic mice carrying myogenin promoter-MRF fusion genes, (ii) Determine which MRF cross- regulatory pathways operate in vivo by analyzing MRF expression patterns in MyoD and Myf-5 knock-out embryos and cell cultures, and (iii) Determine roles of individual MRFs in muscle cell specialization by analyzing how muscle fiber type changes upon alteration of MRF expression patterns in vivo.
|Pavlath, Grace K; Dominov, Janice A; Kegley, Kristy M et al. (2003) Regeneration of transgenic skeletal muscles with altered timing of expression of the basic helix-loop-helix muscle regulatory factor MRF4. Am J Pathol 162:1685-91|