Involvement of CD45 in central nervous system myelination.
Myelin is a multi-layered membranous lipid insulator surrounding axons that allows the rapid conduction of neuronal impulses. In the central nervous system (CNS), myelin is produced by oligodendrocytes. During development, morphologically immature oligodendrocyte precursor cells (OPCs) arise from neural stem cells before differentiating into myelinating oligodendrocytes shortly after birth. Fyn tyrosine kinase (Fyn) has been shown to play a central role during OPC differentiation, including inducing morphological changes in the cells and initiating the expression of myelin basic protein (MBP), a major structural protein required for the compaction of myelin sheaths. Recently, we have shown that signaling via the gamma chain of immunoglobulin Fc receptors (FcRgamma) induces the Fyn-MBP cascade and promotes the morphological differentiation of OPCs. The protein tyrosine phosphatases that are responsible for the positive regulation of Fyn tyrosine kinase activity during this cascade, however, remained unknown. Here we report that a protein tyrosine phosphatase, CD45, is involved in this process. Fyn co-immunoprecipitated with CD45 from differentiating wild-type OPCs in vitro, while CD45-deficient OPCs failed to differentiate. Additionally, dysmyelination was observed in CD45-deficient mice in vivo. Our findings suggest that CD45 is a key phosphatase involved in OPC differentiation and provide a preliminary explanation for the previously reported CD45 mutations observed in some multiple sclerosis (MS) patients.
Nakahara
Jin
J
Department of Anatomy, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. nakaharajin@anet.ne.jp
Seiwa
Chika
C
Tan-Takeuchi
Kyoko
K
Gotoh
Mari
M
Kishihara
Kenji
K
Ogawa
Masaharu
M
Asou
Hiroaki
H
Aiso
Sadakazu
S
D000818:Animals; D000831:Animals, Newborn; D000941:Antigens / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins; D015153:Blotting, Western / Q000379:methods; D002454:Cell Differentiation / Q000187:drug effects; D048429:Cell Size; D002478:Cells, Cultured; D002490:Central Nervous System / Q000166:cytology*; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D007074:Immunoglobulin G / Q000494:pharmacology; D007150:Immunohistochemistry / Q000379:methods; D047468:Immunoprecipitation / Q000379:methods; D017493:Leukocyte Common Antigens / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D004676:Myelin Basic Protein / Q000378:metabolism; D009186:Myelin Sheath / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D000076104:Oligodendrocyte Transcription Factor 2; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism*; D011509:Proteoglycans / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism; D000099216:Chondroitin Sulfate Proteoglycan 4
D000941:Antigens; D051792:Basic Helix-Loop-Helix Proteins; D007074:Immunoglobulin G; D017493:Leukocyte Common Antigens; D004676:Myelin Basic Protein; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D011509:Proteoglycans; D011518:Proto-Oncogene Proteins; D051076:Proto-Oncogene Proteins c-fyn; D019061:src-Family Kinases; D000099216:Chondroitin Sulfate Proteoglycan 4; C512773:Olig2 protein, mouse; C494960:Fyn protein, mouse