The development of glial cells, oligodendrocytes (OL) in CNS and Schwann cells (SC) in PNS, critically depends on axonal contact. Gliogenesis and the phenotype of myelinating glia are regulated by axons. Glial cells promote neuronal survival, regulate the organization of myelinated axons and promote axonal differentiation and myelin sheath production.We recently showed that type III NRG1, a member of the Neuregulin1 (NRG1) family of proteins, is an essential instructive signal for myelination in PNS and directs the ensheathment fate of the axons. We also showed that type III NRG1 promotes CNS myelination and that myelination in CNS and PNS are differentially regulated. Previous studies indicate that membrane bound NRG1 are cleaved by secretases. Upon cleavage in the extracellular region type I and type II NRG1 are released from the neuronal membrane, while type III NRG1 remains tethered on the axonal surface and acts as a juxtacrine signal. The extracellular cleavage is likely to be mediated by the alpha-secretase TACE and by the beta-secretase BACE1. Our studies suggest that type III NRG1 intracellular cleavage is SC dependent and mediated by the gamma-secretase complex.In these studies we will determine the role of these cleavage events in myelination. We will analyze if lentiviruses expressing non-cleavable type III NRG1 can rescue in vitro myelination of type III NRG1 -/- neurons and if non-cleavable type I NRG1 proteins can substitute for type III NRG1. We will also investigate the nature of the molecules regulating NRG1 extracellular cleavage. We will focus on TACE and we will analyze in vitro and in vivo myelination in the absence of TACE. Finally, we will examine if type III NRG1 intracellular cleavage promotes neuronal survival. These studies will provide major insights into the role of type III NRG1 in myelination and will be relevant to develop new therapeutic strategies to promote axonal survival and remyelination.