The (skeletal) muscle regulatory factors (MRFs), of which myoD1 is the prototypical example, are a family of helix-loop proteins which are functionally united by their ability to direct cells from diverse developmental and tissue origins to the skeletal muscle lineage. These factors, however, also act as transcription factors for a subgroup of skeletal muscle-specific genes and exhibit different developmental patterns of expression. To examine this possibility and to elucidate the mechanism(s) by which this could occur, we have chronicled the changes in MRF development, concentrating on the transition between embryonic and fetal stages. This transition involves the switching of contractile protein isoforms from the """"""""cardiac"""""""" to the """"""""skeletal"""""""" type, occurs in concert with increases in nerve-muscle activity, and is associated with increased protein kinase C (PKC) activity. During this period, the level of MRF mRNA for myoD1 and myogenin is also reduced. In noninnervated cultures of skeletal muscle cells, the level of these same MRFs can be reduced by either pharmacologically or genetically elevating PKC activity. Significantly, just as during the embryonic to fetal transition, the levels of """"""""cardiac"""""""" type isoforms are also reduced. All of these genes possess transcriptional regulatory sequences that are targets for myoD1 and myogenin binding. These results suggest that one of the mechanisms responsible for the changes in gene expression during the embryonic to fetal transcription involves downregulation of MRF expression in response to elevated PKC activity. This, in turn, results in transcriptional silencing of a group of genes which utilize the MRFs as obligatory transcription factors. The time course of these events suggest that the effect of PKC on MRF expression may be direct.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Intramural Research (Z01)
Project #
1Z01AG000273-01
Application #
3802243
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
1991
Total Cost
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
United States
Zip Code