down-regulation of myogenin can reverse terminal muscle cell differentiation下调myogenin可以反向终端肌肉细胞分化.pdfVIP

Down-Regulation of Myogenin Can Reverse Terminal Muscle Cell Differentiation 1 1 1 2 Nikolaos P. Mastroyiannopoulos , Paschalis Nicolaou , Mustafa Anayasa , James B. Uney , Leonidas A. Phylactou1* 1 Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus, 2 The Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, United Kingdom Abstract Certain higher vertebrates developed the ability to reverse muscle cell differentiation (dedifferentiation) as an additional mechanism to regenerate muscle. Mammals, on the other hand, show limited ability to reverse muscle cell differentiation. Myogenic Regulatory Factors (MRFs), MyoD, myogenin, Myf5 and Myf6 are basic-helix-loop-helix (bHLH) transcription factors essential towards the regulation of myogenesis. Our current interest is to investigate whether down-regulation of MRFs in terminally differentiated mouse myotubes can induce reversal of muscle cell differentiation. Results from this work showed that reduction of myogenin levels in terminally differentiated mouse myotubes can reverse their differentiation state. Down-regulation of myogenin in terminally differentiated mouse myotubes induces cellular cleavage into mononucleated cells and cell cycle re-entry, as shown by re-initiation of DNA synthesis and increased cyclin D1 and cyclin E2 levels. Finally, we provide evidence that down-regulation of myogenin causes cell cycle re-entry (via down- regulation of MyoD) and cellularisation through separate pathways. These data reveal the important role of myogenin in maintaining te