title: Pleiotrophin suppression of receptor protein tyrosine phosphatase-β/ζ maintains the self-renewal competence of fetal human oligodendrocyte progenitor cells.
abstract: Oligodendrocyte progenitor cells (OPCs) persist in human white matter, yet the mechanisms by which they are maintained in an undifferentiated state are unknown. Human OPCs differentially express protein tyrosine phosphatase receptor β/ζ (PTPRZ1) and its inhibitory ligand, pleiotrophin, suggesting the maintenance of an autocrine loop by which PTPRZ1 activity is tonically suppressed. PTPRZ1 constitutively promotes the tyrosine dephosphorylation of β-catenin and, thus, β-catenin participation in T cell factor (TCF)-mediated transcription. Using CD140a/PDGFRα-based fluorescence-activated cell sorting to isolate fetal OPCs from the fetal brain at gestational ages 16-22 weeks, we asked whether pleiotrophin modulated the expansion of OPCs and, if so, whether this was effected through the serial engagement of PTPRZ1 and β-catenin-dependent signals, such as TCF-mediated transcription. Lentiviral shRNAi knockdown of PTPRZ1 induced TCF-mediated transcription and substantially augmented GSK3β inhibition-induced TCF-reporter luciferase expression, suggesting dual regulation of β-catenin and the importance of PTPRZ1 as a tonic brake upon TCF-dependent transcription. Pharmacological inhibition of GSK3β triggered substrate detachment and initiated sphere formation, yet had no effect on either proliferation or net cell number. In contrast, pleiotrophin strongly potentiated the proliferation of CD140a(+)-sorted OPCs, as did PTPRZ1 knockdown, which significantly increased the total number of population doublings exhibited by OPCs before mitotic senescence. These observations suggest that pleiotrophin inhibition of PTPRZ1 contributes to the homeostatic self-renewal of OPCs and that this process is mediated by the tonic activation of β-catenin/TCF-dependent transcription.
authors.affiliation: Department of Neurology, University of Rochester Medical Center, Rochester, New York 14642, USA.
authors.forename: Crystal R
authors.initials: CR
authors.lastname: McClain
authors.forename: Fraser J
authors.initials: FJ
authors.lastname: Sim
authors.forename: Steven A
authors.initials: SA
authors.lastname: Goldman
mesh_terms: D000704:Analysis of Variance; D001921:Brain / Q000166:cytology; D002352:Carrier Proteins / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003561:Cytarabine / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology*; D003857:Deoxyuridine / Q000031:analogs & derivatives / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005333:Fetus; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D009836:Oligodendroglia / Q000187:drug effects*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000187:drug effects*; D051820:TCF Transcription Factors / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D036341:Intercellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D051820:TCF Transcription Factors; D051176:beta Catenin; D003561:Cytarabine; C066845:pleiotrophin; C022811:edoxudin; D014443:Tyrosine; D020796:Receptor, Platelet-Derived Growth Factor alpha; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; C516895:PTPRZ1 protein, human; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5; D003857:Deoxyuridine