title: Role of Chondroitin Sulfate (CS) Modification in the Regulation of Protein-tyrosine Phosphatase Receptor Type Z (PTPRZ) Activity: PLEIOTROPHIN-PTPRZ-A SIGNALING IS INVOLVED IN OLIGODENDROCYTE DIFFERENTIATION.
abstract: Protein-tyrosine phosphatase receptor type Z (PTPRZ) is predominantly expressed in the developing brain as a CS proteoglycan. PTPRZ has long (PTPRZ-A) and short type (PTPRZ-B) receptor forms by alternative splicing. The extracellular CS moiety of PTPRZ is required for high-affinity binding to inhibitory ligands, such as pleiotrophin (PTN), midkine, and interleukin-34; however, its functional significance in regulating PTPRZ activity remains obscure. We herein found that protein expression of CS-modified PTPRZ-A began earlier, peaking at approximately postnatal days 5-10 (P5-P10), and then that of PTN peaked at P10 at the developmental stage corresponding to myelination onset in the mouse brain. Ptn-deficient mice consistently showed a later onset of the expression of myelin basic protein, a major component of the myelin sheath, than wild-type mice. Upon ligand application, PTPRZ-A/B in cultured oligodendrocyte precursor cells exhibited punctate localization on the cell surface instead of diffuse distribution, causing the inactivation of PTPRZ and oligodendrocyte differentiation. The same effect was observed with the removal of CS chains with chondroitinase ABC but not polyclonal antibodies against the extracellular domain of PTPRZ. These results indicate that the negatively charged CS moiety prevents PTPRZ from spontaneously clustering and that the positively charged ligand PTN induces PTPRZ clustering, potentially by neutralizing electrostatic repulsion between CS chains. Taken altogether, these data indicate that PTN-PTPRZ-A signaling controls the timing of oligodendrocyte precursor cell differentiation in vivo, in which the CS moiety of PTPRZ receptors maintains them in a monomeric active state until its ligand binding.
authors.affiliation: From the Division of Molecular Neurobiology, National Institute for Basic Biology (NIBB) and.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Kuboyama
authors.affiliation: From the Division of Molecular Neurobiology, National Institute for Basic Biology (NIBB) and.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Fujikawa
authors.affiliation: From the Division of Molecular Neurobiology, National Institute for Basic Biology (NIBB) and.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Suzuki
authors.affiliation: From the Division of Molecular Neurobiology, National Institute for Basic Biology (NIBB) and the School of Life Science, Graduate University for Advanced Studies (SOKENDAI), 5-1 Higashiyama, Myodaiji-cho, Okazaki, Aichi 444-8787, Japan.
authors.forename: Naomi
authors.initials: N
authors.lastname: Tanga
authors.affiliation: From the Division of Molecular Neurobiology, National Institute for Basic Biology (NIBB) and the School of Life Science, Graduate University for Advanced Studies (SOKENDAI), 5-1 Higashiyama, Myodaiji-cho, Okazaki, Aichi 444-8787, Japan madon@nibb.ac.jp.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Noda
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002809:Chondroitin Sulfates / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism*; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; C066845:pleiotrophin; D002809:Chondroitin Sulfates; C516895:PTPRZ1 protein, human; C516896:Ptprz1 protein, mouse; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5
keywords: chondroitin sulfate; oligodendrocyte; phosphotyrosine signaling; pleiotrophin; proteoglycan