Soluble neuregulin-1 has bifunctional, concentration-dependent effects on Schwann cell myelination.
Members of the neuregulin-1 (Nrg1) growth factor family play important roles during Schwann cell development. Recently, it has been shown that the membrane-bound type III isoform is required for Schwann cell myelination. Interestingly, however, Nrg1 type II, a soluble isoform, inhibits the process. The mechanisms underlying these isoform-specific effects are unknown. It is possible that myelination requires juxtacrine Nrg1 signaling provided by the membrane-bound isoform, whereas paracrine stimulation by soluble Nrg1 inhibits the process. To investigate this, we asked whether Nrg1 type III provided in a paracrine manner would promote or inhibit myelination. We found that soluble Nrg1 type III enhanced myelination in Schwann cell-neuron cocultures. It improved myelination of Nrg1 type III(+/-) neurons and induced myelination on normally nonmyelinated sympathetic neurons. However, soluble Nrg1 type III failed to induce myelination on Nrg1 type III(-/-) neurons. To our surprise, low concentrations of Nrg1 type II also elicited a similar promyelinating effect. At high doses, however, both type II and III isoforms inhibited myelination and increased c-Jun expression in a manner dependent on Mek/Erk (mitogen-activated protein kinase kinase/extracellular signal-regulated kinase) activation. These results indicate that paracrine Nrg1 signaling provides concentration-dependent bifunctional effects on Schwann cell myelination. Furthermore, our studies suggest that there may be two distinct steps in Schwann cell myelination: an initial phase dependent on juxtacrine Nrg1 signaling and a later phase that can be promoted by paracrine stimulation.
Syed
Neeraja
N
Department of Biological Sciences, Rutgers University, Newark, New Jersey 07102, USA.
Reddy
Kavya
K
Yang
David P
DP
Taveggia
Carla
C
Salzer
James L
JL
Maurel
Patrice
P
Kim
Haesun A
HA
D000818:Animals; D002478:Cells, Cultured; D018920:Coculture Techniques; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005727:Ganglia, Spinal / Q000201:enzymology / Q000378:metabolism; D016758:Genes, jun; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009186:Myelin Sheath / Q000201:enzymology / Q000378:metabolism*; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000201:enzymology / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D051381:Rats; D012583:Schwann Cells / Q000201:enzymology / Q000378:metabolism*; D012584:Sciatic Nerve / Q000201:enzymology / Q000378:metabolism
C094131:NRG1 protein, human; D020890:Neuregulin-1; C490581:Nrg1 protein, mouse; C490580:Nrg1 protein, rat; D020033:Protein Isoforms; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases