Role of the gene PC4/IFRD1 in muscle and neuron regeneration

Muscular dystrophy is a degenerative disease of genetic origin in which the degeneration of the myofiber can be partially compensated by an ongoing process of regeneration, carried out by muscle adult stem cells (satellite cells). In previous studies supported by Telethon we have isolated the gene PC4/IFRD1 (interferon-related develop­ mental regulator 1) and shown by loss-of-function strategies that is required in the process of differentiation of satellite cells. Other laboratories, by means of PC4 null mice, confirmed its requirement in muscle regeneration, showing that the deprivation of PC4 is associated to a dystrophy-like phenotype. The underlying mechanism, as indicated by our recent observations, is based on the fact that PC4 is a target of MyoD and also co-activates MyoD, by displacing from MEF2C the inhibitor histone deacetylase 4 (Micheli et al., 2005). Indeed, MyoD is known to play a key role in triggering muscle regeneration, by acting in concerted action with the MEF2 family of transcriptional regulators. ' Thus, PC4 might act as endogenous inhibitor of histone deacetylases, whose pharmacological inhibitors have been recently shown to be very effective in the treatment of muscle dystrophy in animal models (Minetti et al., 2006). Presently,we are studying the functional significance of PC4 in the process of muscle regeneration. By functional ablation of PC4 in the myoblast by RNA interference we observe that PC4, by regulating the ex­ pression of myogenic factors, is required for the differentiation and exit from cell cycle of myoblasts. Moreover, we have produced a murine transgenic model conditionally overexpressing PC4 in skeletal muscle, in which we observe an increase of muscle regeneration. We are currently analyzing the molecular mechanisms and the possible use of PC4 to increase the myogenic potential of. cells transplanted in muscle dystrophy therapy.