Opposing extracellular signal-regulated kinase and Akt pathways control Schwann cell myelination.
Schwann cells are the myelinating glia of the peripheral nervous system, and their development is regulated by various growth factors, such as neuregulin, platelet-derived growth factor (PDGF), and insulin-like growth factor-I (IGF-I). However, the mechanism of intracellular signaling pathways following these ligand stimuli in Schwann cell differentiation remains elusive. Here, we demonstrate that in cultured Schwann cells, neuregulin and PDGF suppressed the expression of myelin-associated protein markers, whereas IGF-I promoted it. Although these ligands activated common downstream signaling pathways [i.e., extracellular signal-regulated kinase (Erk) and phosphatidylinositol-3-kinase (PI3K)-Akt pathways], the profiles of activation varied among ligands. To elucidate the function of these pathways and the mechanisms underlying Schwann cell differentiation, we used adenoviral vectors to selectively activate or inactivate these pathways. We found that the selective activation of Erk pathways suppressed Schwann cell differentiation, whereas that of PI3K pathways promoted it. Furthermore, lithium chloride, a modulator of glycogen synthase kinase-3beta (GSK-3beta) promoted Schwann cell differentiation, suggesting the involvement of GSK-3beta as a downstream molecule of PI3K-Akt pathways. Selective activation of PI3K pathways in Schwann cells by gene transfer also demonstrated increased myelination in in vitro Schwann cell-DRG neuron cocultures and in vivo allogenic nerve graft experiments. We conclude that signals mediated by PI3K-Akt are crucial for initiation of myelination and that the effects of growth factors are primarily dependent on the balance between Erk and PI3K-Akt activation. Our results also propose the possibility of augmenting Schwann cell functions by modulating intracellular signals in light of future cell therapies.
Ogata
Toru
T
Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Iijima
Satoru
S
Hoshikawa
Shinya
S
Miura
Toshiki
T
Yamamoto
Shin-ichi
S
Oda
Hiromi
H
Nakamura
Kozo
K
Tanaka
Sakae
S
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D018920:Coculture Techniques; D005576:Colforsin / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000502:physiology*; D005727:Ganglia, Spinal / Q000166:cytology; D005786:Gene Expression Regulation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000187:drug effects / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D018021:Lithium Chloride / Q000494:pharmacology; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000502:physiology; D004676:Myelin Basic Protein / Q000096:biosynthesis / Q000235:genetics; D018993:Myelin P0 Protein / Q000096:biosynthesis / Q000235:genetics; D009186:Myelin Sheath / Q000502:physiology*; D018992:Myelin-Associated Glycoprotein / Q000096:biosynthesis / Q000235:genetics; D020890:Neuregulin-1 / Q000494:pharmacology; D009475:Neurons, Afferent / Q000166:cytology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017208:Rats, Wistar; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012583:Schwann Cells / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D012584:Sciatic Nerve / Q000166:cytology / Q000637:transplantation*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014184:Transplantation, Homologous; D018631:ras Proteins / Q000502:physiology
D005576:Colforsin; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D007334:Insulin-Like Growth Factor I; D018021:Lithium Chloride; D048369:MAP Kinase Kinase 1; D004676:Myelin Basic Protein; D018993:Myelin P0 Protein; D018992:Myelin-Associated Glycoprotein; D020890:Neuregulin-1; D019869:Phosphatidylinositol 3-Kinases; D010982:Platelet-Derived Growth Factor; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011993:Recombinant Fusion Proteins; D018631:ras Proteins; C494920:Akt1 protein, rat; C000605508:Gsk3b protein, rat