Inactivation of Protein Tyrosine Phosphatase Receptor Type Z by Pleiotrophin Promotes Remyelination through Activation of Differentiation of Oligodendrocyte Precursor Cells.
Multiple sclerosis (MS) is a progressive neurological disorder associated with myelin destruction and neurodegeneration. Oligodendrocyte precursor cells (OPCs) present in demyelinated lesions gradually fail to differentiate properly, so remyelination becomes incomplete. Protein tyrosine phosphatase receptor type Z (PTPRZ), one of the most abundant protein tyrosine phosphatases expressed in OPCs, is known to suppress oligodendrocyte differentiation and maintain their precursor cell stage. In the present study, we examined the in vivo mechanisms for remyelination using a cuprizone-induced demyelination model. Ptprz-deficient and wild-type mice both exhibited severe demyelination and axonal damage in the corpus callosum after cuprizone feeding. The similar accumulation of OPCs was observed in the lesioned area in both mice; however, remyelination was significantly accelerated in Ptprz-deficient mice after the removal of cuprizone. After demyelination, the expression of pleiotrophin (PTN), an inhibitory ligand for PTPRZ, was transiently increased in mouse brains, particularly in the neurons involved, suggesting its role in promoting remyelination by inactivating PTPRZ activity. In support of this view, oligodendrocyte differentiation was augmented in a primary culture of oligodendrocyte-lineage cells from wild-type mice in response to PTN. In contrast, these cells from Ptprz-deficient mice showed higher oligodendrocyte differentiation without PTN and differentiation was not enhanced by its addition. We further demonstrated that PTN treatment increased the tyrosine phosphorylation of p190 RhoGAP, a PTPRZ substrate, using an established line of OPCs. Therefore, PTPRZ inactivation in OPCs by PTN, which is secreted from demyelinated axons, may be the mechanism responsible for oligodendrocyte differentiation during reparative remyelination in the CNS.


CONCLUSIONS
Multiple sclerosis (MS) is an inflammatory disease of the CNS that destroys myelin, the insulation that surrounds axons. Associated damages to oligodendrocytes (the cells that produce myelin) and nerve fibers produce neurological disability. Most patients with MS have an initial relapsing-remitting course for 5-15 years. Remyelination during the early stages of the disease process has been documented; however, the molecular mechanism underlying remyelination has not been understood. Protein tyrosine phosphatase receptor type Z (PTPRZ) is a receptor-like protein tyrosine phosphatase preferentially expressed in the CNS. This study shows that pleiotrophin, an inhibitory ligand for PTPRZ, is transiently expressed and released from demyelinated neurons to inactivate PTPRZ in oligodendrocyte precursor cells present in the lesioned part, thereby allowing their differentiation for remyelination.
Division of Molecular Neurobiology, National Institute for Basic Biology, and.
Kazuya
K
Kuboyama
Division of Molecular Neurobiology, National Institute for Basic Biology, and.
Akihiro
A
Fujikawa
Division of Molecular Neurobiology, National Institute for Basic Biology, and.
Ryoko
R
Suzuki
Division of Molecular Neurobiology, National Institute for Basic Biology, and School of Life Science, The Graduate University for Advanced Studies (SOKENDAI), Okazaki, Aichi 444-8787, Japan madon@nibb.ac.jp.
Masaharu
http://orcid.org/0000-0002-3796-524X
M
Noda
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D000941:Antigens / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D003337:Corpus Callosum / Q000473:pathology; D003471:Cuprizone / Q000633:toxicity; D016207:Cytokines / Q000378:metabolism*; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D004676:Myelin Basic Protein / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects / Q000502:physiology*; D011509:Proteoglycans / Q000378:metabolism; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5 / Q000172:deficiency* / Q000235:genetics; D013234:Stem Cells; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics; D000099216:Chondroitin Sulfate Proteoglycan 4
D016564:Amyloid beta-Protein Precursor; D000941:Antigens; D002352:Carrier Proteins; D003471:Cuprizone; D016207:Cytokines; D004676:Myelin Basic Protein; D009419:Nerve Tissue Proteins; D011509:Proteoglycans; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5; D016159:Tumor Suppressor Protein p53; D000099216:Chondroitin Sulfate Proteoglycan 4; C066845:pleiotrophin; C516896:Ptprz1 protein, mouse
PTPRZ; multiple sclerosis; oligodendrocyte; pleiotrophin; remyelination; tyrosine phosphorylation