NRG-1 Type III Instructs Schwann Cells

Abstract

Schwann cells can form Remak bundles ensheathing multiple, small unmyelinated axons or can form thick or thin myelin sheaths around axons. Generally, the size of the axons correlates with their ensheathment or myelination: the thicker the axon, the thicker the myelin. Taveggia et al . now show that neuregulin-1 (NRG-1) type III serves as a signal to the Schwann cells, with low concentrations of NRG-1 type III in the neuron leading to ensheathment and high concentrations leading to thick myelination. In cultures of rat Schwann cells with dorsal root ganglion (DRG) neurons from wild-type or NRG1 type III —/— mice, the Schwann cells robustly myelinated the wild-type neurites but failed to myelinate the NRG-1 type III-deficient neurites. Forced expression of NRG-1 type III in the deficient DRG cells allowed the Schwann cells to myelinate the neurites, and in some cases the myelin was as much as twice as thick as that surrounding the wild-type neurites. Analysis of the abundance of NRG-1 type III in cells that typically form Remak bundles [nerve-growth factor (NGF)-dependent sympathetic neurons from superior cervical ganglia], are thinly myelinated (NGF-dependent neurons of the DRG), or are thickly myelinated [brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT3)-dependent neurons of the DRG] showed that NRG-1 type III abundance was highest in the BDNF and NT3-dependent neurons and lowest (barely detectable) in the SCG neurons. Forced expression of NRG-1 type III in the SCG neurons promoted myelination of these neurons in Schwann cell coculture experiments. Although NRG-1 type III was necessary for myelination, it was not sufficient, because expression of NRG-1 type III in Chinese hamster ovary cells did not promote myelination or ensheathment of these cells. Consistent with a threshold effect of NRG-1 type III, NRG1 type III —/+ mice exhibit abnormalities in Remak bundles and hypomyelination due to thinner myelin and a decreased number of myelinated axons. NRG-1 type III was present on the surface of the axons based on ligand-binding analysis of cultured neurons, and a soluble form of the ectodomain of NRG-1 type III was not able to promote myelination of NRG-1 type III-deficient neurons. Thus, NRG-1 type III appears to serve as an instructive juxtacrine signal on the axon surface for Schwann cell ensheathment or myelination. C. Taveggia, G. Zanazzi, A. Petrylak, H. Yano, J. Rosenbluth, S. Einheber, X. Xu, R. M. Esper, J. A. Loeb, P. Shrager, M. V. Chao, D. L. Falls, L. Role, J. L. Salzer, Neuregulin-1 type III determines the ensheathment fate of axons. Neuron 47 , 681-694 (2005). [PubMed]