Soluble Neuregulin and Schwann Cell Myelination: a Therapeutic Potential for Improving Remyelination of Adult Axons

Abstract

Myelination in the peripheral nervous system (PNS) is induced by close contact signaling between axons and Schwann cells. Previous studies have identified membrane-bound neuregulin-1 (Nrg1) type III, expressed on the axons, as the key instructive signal that regulates Schwann cell myelination. In our recent study, we show that recombinant soluble Nrg1 elicits a similar pro-myelinating effect on Schwann cells, albeit in a dosage-dependent manner: Nrg1 promotes myelination at low concentrations but inhibits it at high concentrations. The inhibitory effect of Nrg1 is mediated through its activation of the Ras/Raf/Erk pathway in Schwann cells, and inhibition of the pathway using a pharmacologic inhibitor restores myelination. We also show that soluble Nrg1 enhances myelination on axons that do not express sufficient amount of Nrg1 type III needed for robust myelination. These findings are significant as they suggest that combined therapies aimed at enhancing Nrg1 signaling and blocking the Ras/Raf/Erk activation may be an effective strategy for improving remyelination on adult axons, which, as shown in our recent data, express low levels of Nrg1 type III. In this report we provide an overview of our recent findings and discuss the therapeutic potential of soluble Nrg1.

Figure 1. Expression of Nrg1 type III in adult and embryonic neurons

(A) Cell lysates were prepared from adult and embryonic neuron cultures and subjected to Western blotting. The expression of Nrg1 type III was reduced in adult compared to embryonic neurons. (B) Quantification of the result shown in (A).

Figure 2. Activation of ErbB2 and Akt in Schwann cells induced by membrane fractions prepared from adult and embryonic neurons

Neurite membrane fractions were prepared from adult and embryonic neurons and added onto Schwann cells. After 20 minutes, cell lysates were prepared and subjected to Western blot analysis. Control Schwann cell cultures were treated with soluble Nrg1. NT: no treatment. The levels of erbB2 and Akt activation are much lower in Schwann cells treated with adult neurite membranes.