The role of Nrg1-ErbB signaling in promoting Schwann cell myelination

Myelination is important for rapid saltatory conduction of nerve signals along the axons. Under various pathological conditions, myelin is lost and rebuilding myelin is required for functional recovery. In the PNS, myelination is regulated by axonal signals. Therefore, enhancing the promyelinating signals could be used as a therapeutic strategy to improve myelin repair by endogenous or transplanted myelinating glial cells such as Schwann cells. Recent studies identified Nrg1-type III as an important promyelinating signal that regulate Schwann cell myelination. Therefore, we hypothesized that providing an ectopic Nrg1-type III signal in a soluble form would increase the myelinating potential of Schwann cells. Since Nrg1-type III is normally expressed by axons as a membrane bound protein, in Aim 1 we first characterized the signaling function and the therapeutic potential of soluble Nrg1-type III in Schwann cells. Results from this study show that soluble Nrg1-type III elicits a promyelinating effect in-vitro: it increases myelin gene expression and enhances myelination on axons that express low levels of Nrg1-type III. However, when used at high concentrations it has a contrasting effect and inhibits myelination. Remyelination in the adult PNS is often incomplete: the myelin segments are thin and short. To determine the cell type that contributes to the defect, we characterized the myelination potentials of Schwann cells and neurons isolated from adult PNS in Aim 2. Results show that while adult Schwann cells myelinate normally, the axons provide insufficient promyelinating signals by expressing low levels of Nrg1-type III. In Aim 3, we investigated whether providing ectopic Nrg1-type III improves myelination on adult axons. Surprisingly, neither treatment with soluble nor over expressing membrane bound Nrg1-type III was sufficient to enhance myelination on adult axons. Further analysis revealed that adult axons increases Erk1/2 activity in the associated Schwann cells, an inhibitory signal for myelination. Inhibiting those signals significantly increase myelination on adult axons.