MOLECULAR PATHWAYS OF MUSCLE DE-DIFFERENTIATION

Regeneration is a striking feature of amphibians which, upon limb or tail amputation, are able to perfectly re-build the lost appendage. A key role in this striking regeneration ability is the process of "de-differentiation": following a wound, higly specialized and differentiated cells, such as those in the muscle fibers, regresses from their terminally differentiated state and produce "progenitor" cells that can exit the muscle and move to the zone below the wound plane. Here they contribute to the formation of a special tissue, the "regenerative blastema", giving rise to the substitute structure that, at the end of the process, will be identical to the original one. For unknown reasons, this ability has been lost by mammals, which, infact, show a very limited regenerative response. Recently it has been shown that factors present in regenerating amphibian tissues are able to stimulate de-differentiation of mammalian muscle fibers, indicating the possibility to "switch on" again the regenerative process also in these animals. The identity of these factors is still unknown. The aim of this project is to 1) Identify the genetic machinery responsible for production of de-differentiation factors and their mechanism of action 2) Understand why this machinery is silenced in mammals The understanding of these mechanisms will be of outstanding importance to acquire a wider knowledge of regeneration processes. Other than that, the possibility to produce muscle "progenitor" cells, able to substitute the diseased fiber, will open novel therapeutic perspectives to cure degenerative diseases such as muscular dystrophy.