Abstract
Gene expression in skeletal muscle is regulated by the firing pattern of motor neurons, but the signalling systems involved in excitation–transcription coupling are unknown. Here, using in vivo transfection in regenerating muscle, we show that constitutively active Ras and a Ras mutant that selectively activates the MAPK(ERK) pathway are able to mimic the effects of slow motor neurons on expression of myosin genes. Conversely, the effect of slow motor neurons is inhibited by a dominant-negative Ras mutant. MAPK(ERK) activity is increased by innervation and by low-frequency electrical stimulation. These results indicate that Ras–MAPK signalling is involved in promoting nerve-activity-dependent differentiation of slow muscle fibres in vivo.
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Acknowledgements
This work was supported by grants from the European Commission (BIOTECH contract number ERBBIO4CT960216), the Giovanni Armenise–Harvard Foundation for Advanced Scientific Research, Telethon-Italy, the Italian Space Agency (ASI) and the Italian Ministry of University and Scientific and Technological Research (MURST). A.L.S. is a TMR Marie Curie research training grant recipient. We thank A. Hall, E. Taparowski and S. Alemà for Ras mutants; J.S. Gutkind for HA–ERK; R. Kitsis for MyHC-slow promoter-luciferase; R.S. Williams for myoglobin–luciferase; T. Pozzan, P.P. di Fiore and G. Scita for discussions; and A. Picard for help with some experiments.
Correspondence and requests for materials should be addressed to S.S.
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Murgia, M., Serrano, A., Calabria, E. et al. Ras is involved in nerve-activity-dependent regulation of muscle genes. Nat Cell Biol 2, 142–147 (2000). https://doi.org/10.1038/35004013
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DOI: https://doi.org/10.1038/35004013
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