Gliogenesis and the phenotype of myelinating glia critically depend on axonal contacts. Glial cells promote neuronal survival, regulate the organization of myelinated axons and promote axonal differentiation and myelin sheath production. We previously showed that axonal NRG1 type III, a member of the Neuregulin-1 (NRG1) family of proteins, is an essential instructive signal that directs axon sorting, ensheathment and myelination in the PNS.

All NRG1 proteins are activated by proteases-mediated extracellular cleavage. The extracellular cleavage of NRG1 type III is mediated by the a-secretase TACE and the b-secretase BACE1. While BACE1 cleavage of NRG1 type III promotes myelination, we recently reported that TACE cleaves NRG1 and inhibits myelination by competing with BACE1, thus identifying a novel mechanism regulating PNS myelination. In vitro knockdown, and in vivo ablation of neuronal TACE accelerates the onset of myelination and results in hypermyelination and aberrant myelination of small caliber fibers. Further, the inhibitory effect of TACE is neuron autonomous as Schwann cells lacking TACE elaborate myelin of normal myelin thickness.

Thus, secretases regulate the level of NRG1 type III at the axonal membrane and suggest the existence of post-transcriptional mechanism(s) regulating the abundance and function of NRG1. Finally, our studies identify secretases as a potential therapeutic target to modulate myelination.