ROLE OF THE GENE PC4/IFRD1 IN MUSCLE AND NEURON REGENERATION

Muscular dystrophy is a degenerative disease of genetic origin in which the myofiber – the basic contractile component of muscle - undergoes degeneration and death. This phenomenon, which leads to replacement of muscle fibers by fibrous tissue unable to contract, is however contrasted by an ongoing regeneration carried out by satellite cells. These cells, which reside at the margin of the myofiber, are the stem cells of adult muscle and have the ability to divide after muscle damage and to regenerate the muscle. It has been demonstrated that the gene MyoD plays a key role in this process by directing the differentiation of satellite cells. Transplantation of satellite cells is a method experienced, mostly in the case of the Duchenne muscular dystrophy, to substitute the damaged muscle. With the support of Telethon, we have isolated in the past years a gene – PC4/IFRD1 – which, as shown by our laboratory and by others, is required in the process of differentiation of satellite cells and in the regeneration of muscle. We have recently demonstrated that the molecular mechanism of action of PC4 resides in its ability to potentiate the activity of MyoD, by stimulating the function of an important factor that cooperates with MyoD: MEF2C. Moreover, PC4 is a direct target of MyoD, which induces its expression. Thus, we expect that PC4 in vivo may stimulate the existing satellite cells to generate new muscle. The project that we propose aims to verify this hypothesis by producing a mouse model overexpressing PC4. This model will enable us to directly test whether PC4 can increase the regenerative potential of a damaged muscle in normal animals as well as in mice models for Duchenne dystrophy, after interbreeding. These studies, accompanied by further investigations on the molecular mechanisms of PC4, will tell us whether the control of PC4 activity can be of therapeutic usefulness to improve the low regenerative efficiency of transplanted satellite cells.