Roles of meltrin-beta/ADAM19 in progression of Schwann cell differentiation and myelination during sciatic nerve regeneration.
Remyelination is an important aspect of nerve regeneration after nerve injury, but the underlying mechanisms are not fully understood. Here, we show that meltrin-beta (ADAM19), a member of the ADAM (a disintegrin and metalloprotease) family, plays crucial roles in nerve regeneration after a crush injury to the sciatic nerves. The expression of meltrin-beta was up-regulated in neurons after the crush injury. Morphometrical analysis revealed a delay in remyelination in meltrin-beta-deficient nerves, whereas no significant defects were observed in their axon elongation. The activation of Krox-20, an indispensable transcription factor for myelination, was delayed in meltrin-beta-deficient nerves and was accompanied by the retarded expression of myelin-related proteins. Expression of Krox-20 in Schwann cells was mediated by Akt. Phosphorylation of Akt but not that of Erks was reduced in regenerating nerves of meltrin-beta-deficient mice. The cell membrane fraction prepared from meltrin-beta-deficient nerves showed a defective activation of Akt in the membrane-loaded Schwann cells. Meltrin-beta-deficient mice exhibited delayed sciatic functional recovery after the nerve crush. Altogether, these results reveal a role of meltrin-beta in Schwann cell differentiation and re-myelination in nerve regeneration. Moreover, this study suggests that meltrin-beta functions as a modulator of juxtacrine signaling from axons that activate the Akt pathway and the Krox-20 expression, which is the prerequisite for Schwann cell differentiation.
Wakatsuki
Shuji
S
Department of Growth Regulation, Institute for Frontier Medical Sciences, Kyoto University, Kawahara-cho 53, Shogo-in, Kyoto 606-8507, Japan; Department of Peripheral Nervous System Research, National Institute of Neuroscience, National Center for Neurology and Psychiatry, 4-1-1 Ogawahigashi-cho, Kodaira 187-8502, Japan.
Yumoto
Norihiro
N
Department of Growth Regulation, Institute for Frontier Medical Sciences, Kyoto University, Kawahara-cho 53, Shogo-in, Kyoto 606-8507, Japan.
Komatsu
Koji
K
Department of Growth Regulation, Institute for Frontier Medical Sciences, Kyoto University, Kawahara-cho 53, Shogo-in, Kyoto 606-8507, Japan.
Araki
Toshiyuki
T
Department of Peripheral Nervous System Research, National Institute of Neuroscience, National Center for Neurology and Psychiatry, 4-1-1 Ogawahigashi-cho, Kodaira 187-8502, Japan.
Sehara-Fujisawa
Atsuko
A
Department of Growth Regulation, Institute for Frontier Medical Sciences, Kyoto University, Kawahara-cho 53, Shogo-in, Kyoto 606-8507, Japan. Electronic address: asehara@frontier.kyoto-u.ac.jp.
D051722:ADAM Proteins / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001522:Behavior, Animal; D002454:Cell Differentiation / Q000502:physiology*; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000502:physiology*; D009416:Nerve Regeneration / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012583:Schwann Cells / Q000166:cytology*; D012584:Sciatic Nerve / Q000502:physiology*; D015398:Signal Transduction
D034741:RNA, Small Interfering; D051057:Proto-Oncogene Proteins c-akt; D051722:ADAM Proteins; C096116:Adam19 protein, mouse