Inactivation of Protein Tyrosine Phosphatase Receptor Type Z by Pleiotrophin Promotes Remyelination through Activation of Differentiation of Oligodendrocyte Precursor Cells

Abstract

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.Key words: multiple sclerosis; oligodendrocyte; pleiotrophin; PTPRZ; remyelination; tyrosine phosphorylation Significance StatementMultiple 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.

Role of Chondroitin Sulfate (CS) Modification in the Regulation of Protein-tyrosine Phosphatase Receptor Type Z (PTPRZ) Activity

“…PTPRZ dephosphorylates p190 RhoGAP, thereby acting as a counterpart of FYN (11,12). The amounts of myelin basic protein (MBP) and myelinated axons in the brain at postnatal day 10, when myelination occurs, are significantly higher in Ptprz-deficient mice than in wildtype animals, indicating a suppressive role for PTPRZ in oligodendrocyte differentiation (11).…”

“…PTN has been shown to inactivate the intracellular catalytic activity of PTPRZ-B by inducing molecular oligomerization in baby hamster kidney (BHK)-21 cells (22). We recently demonstrated that PTN enhanced thyroid hormone-induced OPC differentiation in a primary culture of glial cells from wild-type mice, but not Ptprzdeficient mice, indicating that its effects are mediated by PTPRZ (12,25). We established the oligodendrocyte-lineage cell line, OL1, from the p53-knock-out mouse brain (12).…”

“…We recently demonstrated that PTN enhanced thyroid hormone-induced OPC differentiation in a primary culture of glial cells from wild-type mice, but not Ptprzdeficient mice, indicating that its effects are mediated by PTPRZ (12,25). We established the oligodendrocyte-lineage cell line, OL1, from the p53-knock-out mouse brain (12). Immature OL1 cells are neural/glial antigen 2 chondroitin sulfate (NG2) proteoglycan-positive OPC-like cells that express PTPRZ-A and PTPRZ-B as CS proteoglycans; however, their expression decreases after differentiation into oligodendrocytes, although PTPRZ-B remains weakly detectable (12).…”

“…We established the oligodendrocyte-lineage cell line, OL1, from the p53-knock-out mouse brain (12). Immature OL1 cells are neural/glial antigen 2 chondroitin sulfate (NG2) proteoglycan-positive OPC-like cells that express PTPRZ-A and PTPRZ-B as CS proteoglycans; however, their expression decreases after differentiation into oligodendrocytes, although PTPRZ-B remains weakly detectable (12). Immature OL1 cells treated with PTN show increased p190 RhoGAP phosphorylation and significantly enhanced thyroid hormone-induced differentiation to oligodendrocytes (12).…”

“…Immature OL1 cells are neural/glial antigen 2 chondroitin sulfate (NG2) proteoglycan-positive OPC-like cells that express PTPRZ-A and PTPRZ-B as CS proteoglycans; however, their expression decreases after differentiation into oligodendrocytes, although PTPRZ-B remains weakly detectable (12). Immature OL1 cells treated with PTN show increased p190 RhoGAP phosphorylation and significantly enhanced thyroid hormone-induced differentiation to oligodendrocytes (12). Therefore, we postulated that the catalytic activity of PTPRZ maintains OPCs in an undifferentiated state, and PTN-induced PTPRZ inactivation releases this blockage of cellular differentiation (12).…”