Journal of Molecular Neuroscience

, Volume 62, Issue 3–4, pp 329–343 | Cite as

Glial and Neuronal Protein Tyrosine Phosphatase Alpha (PTPα) Regulate Oligodendrocyte Differentiation and Myelination

  • Yuda Shih
  • Philip T. T. Ly
  • Jing Wang
  • Catherine J. PallenEmail author


CNS myelination defects occur in mice deficient in receptor-like protein tyrosine phosphatase alpha (PTPα). Here, we investigated the role of PTPα in oligodendrocyte differentiation and myelination using cells and tissues from wild-type (WT) and PTPα knockout (KO) mice. PTPα promoted the timely differentiation of neural stem cell-derived oligodendrocyte progenitor cells (OPCs). Compared to WT OPCs, KO OPC cultures had more NG2+ progenitors, fewer myelin basic protein (MBP)+ oligodendrocytes, and reduced morphological complexity. In longer co-cultures with WT neurons, more KO than WT OPCs remained NG2+ and while equivalent MBP+ populations of WT and KO cells formed, the reduced area occupied by the MBP+ KO cells suggested that their morphological maturation was impeded. These defects were associated with reduced myelin formation in KO OPC/WT neuron co-cultures. Myelin formation was also impaired when WT OPCs were co-cultured with KO neurons, revealing a novel role for neuronal PTPα in myelination. Canonical Wnt/β-catenin signaling is an important regulator of OPC differentiation and myelination. Wnt signaling activity was not dysregulated in OPCs lacking PTPα, but suppression of Wnt signaling by the small molecule XAV939 remediated defects in KO oligodendrocyte differentiation and enhanced myelin formation by KO oligodendrocytes. However, the myelin segments that formed were significantly shorter than those produced by WT oligodendrocytes, raising the possibility of a role for glial PTPα in myelin extension distinct from its pro-differentiating actions. Altogether, this study reveals PTPα as a molecular coordinator of oligodendroglial and neuronal signals that controls multiple aspects of oligodendrocyte development and myelination.


Protein tyrosine phosphatase alpha Oligodendrocyte maturation Myelination Remediation 



This work was supported by grants 1129 and 2366 from the Multiple Sclerosis Society of Canada (to C.J.P.). P.T.T.L is the recipient of a Postdoctoral Fellowship from the Canadian Institutes of Health Research, and C.J.P. holds an Investigator Award from the BC Children’s Hospital Research Institute. We thank Dr. Chinten James Lim for valuable assistance with imaging quantification.

Compliance with Ethical Standards

Animal care and use followed the guidelines of the University of British Columbia (UBC) and the Canadian Council on Animal Care, and were reviewed and approved by UBC.

Supplementary material

12031_2017_941_MOESM1_ESM.pdf (98 kb)
ESM 1 (PDF 97 kb)


  1. Bercury KK, Macklin WB (2015) Dynamics and mechanisms of CNS myelination. Dev Cell 32(4):447–458CrossRefPubMedGoogle Scholar
  2. Bodrikov V, Leshchyns'ka I, Sytnyk V, Overvoorde J, den Hertog J, Schachner M (2005) RPTPalpha is essential for NCAM-mediated p59fyn activation and neurite elongation. J Cell Biol 168(1):127–139CrossRefPubMedPubMedCentralGoogle Scholar
  3. Buttermore ED, Thaxton CL, Bhat MA (2013) Organization and maintenance of molecular domains in myelinated axons. J Neurosci Res 91(5):603–622CrossRefPubMedPubMedCentralGoogle Scholar
  4. Chang KJ, Rasband MN (2013) Excitable domains of myelinated nerves: axon initial segments and nodes of Ranvier. Curr Top Membr 72:159–192CrossRefPubMedGoogle Scholar
  5. Chen Y, Balasubramaniyan V, Peng J, Hurlock EC, Tallquist M, Li J, Lu QR (2007) Isolation and culture of rat and mouse oligodendrocyte precursor cells. Nat Protoc 2(5):1044–1051CrossRefPubMedGoogle Scholar
  6. Fancy SP, Harrington EP, Yuen TJ, Silbereis JC, Zhao C, Baranzini SE, Bruce CC, Otero JJ, Huang EJ, Nusse R, Franklin RJ, Rowitch DH (2011) Axin2 as regulatory and therapeutic target in newborn brain injury and remyelination. Nat Neurosci 14(8):1009–1016CrossRefPubMedPubMedCentralGoogle Scholar
  7. Guo F, Lang J, Sohn J, Hammond E, Chang M, Pleasure D (2015) Canonical Wnt signaling in the oligodendroglial lineage-puzzles remain. Glia 63(10):1671–1693Google Scholar
  8. Hill RA, Medved J, Patel KD, Nishiyama A (2014) Organotypic slice cultures to study oligodendrocyte dynamics and myelination. Journal of visualized experiments : JoVE 90:e51835Google Scholar
  9. Huang SM, Mishina YM, Liu S, Cheung A, Stegmeier F, Michaud GA, Charlat O, Wiellette E, Zhang Y, Wiessner S, Hild M, Shi X, Wilson CJ, Mickanin C, Myer V, Fazal A, Tomlinson R, Serluca F, Shao W, Cheng H, Shultz M, Rau C, Schirle M, Schlegl J, Ghidelli S, Fawell S, Lu C, Curtis D, Kirschner MW, Lengauer C, Finan PM, Tallarico JA, Bouwmeester T, Porter JA, Bauer A, Cong F (2009) Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 461(7264):614–620CrossRefPubMedGoogle Scholar
  10. Hurtado de Mendoza T, Balana B, Slesinger PA, Verma IM (2011) Organotypic cerebellar cultures: apoptotic challenges and detection. J Vis Exp (51):e2564 doi: 10.3791/2564
  11. Imada S, Murata Y, Kotani T, Hatano M, Sun C, Konno T, Park JH, Kitamura Y, Saito Y, Ohdan H, Matozaki T. 2016. Role of Src family kinases in regulation of intestinal epithelial homeostasis. Mol Cell Biol 36(22):2811–2823Google Scholar
  12. Kerman BE, Kim HJ, Padmanabhan K, Mei A, Georges S, Joens MS, Fitzpatrick JA, Jappelli R, Chandross KJ, August P, Gage FH (2015) In vitro myelin formation using embryonic stem cells. Development 142(12):2213–2225CrossRefPubMedPubMedCentralGoogle Scholar
  13. Lee Y, Morrison BM, Li Y, Lengacher S, Farah MH, Hoffman PN, Liu Y, Tsingalia A, Jin L, Zhang PW, Pellerin L, Magistretti PJ, Rothstein JD (2012) Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature 487(7408):443–448CrossRefPubMedPubMedCentralGoogle Scholar
  14. Lee HK, Chaboub LS, Zhu W, Zollinger D, Rasband MN, Fancy SP, Deneen B (2015) Daam2-PIP5K is a regulatory pathway for Wnt signaling and therapeutic target for remyelination in the CNS. Neuron 85(6):1227–1243CrossRefPubMedPubMedCentralGoogle Scholar
  15. Maldonado PP, Angulo MC (2015) Multiple modes of communication between neurons and oligodendrocyte precursor cells. Neuroscientist 21(3):266–276Google Scholar
  16. Nave KA (2010) Myelination and support of axonal integrity by glia. Nature 468(7321):244–252CrossRefPubMedGoogle Scholar
  17. Nave KA, Werner HB (2014) Myelination of the nervous system: mechanisms and functions. Annu Rev Cell Dev Biol 30:503–533CrossRefPubMedGoogle Scholar
  18. O’Meara RW, Ryan SD, Colognato H, Kothary R (2011) Derivation of enriched oligodendrocyte cultures and oligodendrocyte/neuron myelinating co-cultures from post-natal murine tissues. J Vis Exp (54):e3324. doi: 10.3791/3324
  19. Pallen CJ (2003) Protein tyrosine phosphatase alpha (PTPalpha): a Src family kinase activator and mediator of multiple biological effects. Curr Top Med Chem 3(7):821–835CrossRefPubMedGoogle Scholar
  20. Pedraza CE, Monk R, Lei J, Hao Q, Macklin WB (2008) Production, characterization, and efficient transfection of highly pure oligodendrocyte precursor cultures from mouse embryonic neural progenitors. Glia 56(12):1339–1352CrossRefPubMedPubMedCentralGoogle Scholar
  21. Ponniah S, Wang DZ, Lim KL, Pallen CJ (1999) Targeted disruption of the tyrosine phosphatase PTPalpha leads to constitutive downregulation of the kinases Src and Fyn. Curr Biol 9(10):535–538CrossRefPubMedGoogle Scholar
  22. Rossol-Allison J, Stemmle LN, Swenson-Fields KI, Kelly P, Fields PE, McCall SJ, Casey PJ, Fields TA (2009) Rho GTPase activity modulates Wnt3a/beta-catenin signaling. Cell Signal 21(11):1559–1568CrossRefPubMedPubMedCentralGoogle Scholar
  23. Sap J, D'Eustachio P, Givol D, Schlessinger J (1990) Cloning and expression of a widely expressed receptor tyrosine phosphatase. Proc Natl Acad Sci U S A 87(16):6112–6116CrossRefPubMedPubMedCentralGoogle Scholar
  24. Sharifi K, Ebrahimi M, Kagawa Y, Islam A, Tuerxun T, Yasumoto Y, Hara T, Yamamoto Y, Miyazaki H, Tokuda N, Yoshikawa T, Owada Y (2013) Differential expression and regulatory roles of FABP5 and FABP7 in oligodendrocyte lineage cells. Cell Tissue Res 354(3):683–695CrossRefPubMedGoogle Scholar
  25. Simons M, Trajkovic K (2006) Neuron-glia communication in the control of oligodendrocyte function and myelin biogenesis. J Cell Sci 119(Pt 21):4381–4389CrossRefPubMedGoogle Scholar
  26. Su J, Muranjan M, Sap J (1999) Receptor protein tyrosine phosphatase alpha activates Src-family kinases and controls integrin-mediated responses in fibroblasts. Curr Biol 9(10):505–511CrossRefPubMedGoogle Scholar
  27. Tiran Z, Peretz A, Sines T, Shinder V, Sap J, Attali B, Elson A (2006) Tyrosine phosphatases epsilon and alpha perform specific and overlapping functions in regulation of voltage-gated potassium channels in Schwann cells. Mol Biol Cell 17(10):4330–4342CrossRefPubMedPubMedCentralGoogle Scholar
  28. Wang PS, Wang J, Xiao ZC, Pallen CJ (2009) Protein tyrosine phosphatase alpha (PTP{alpha}) acts as an upstream regulator of Fyn signaling to promote oligodendrocyte differentiation and myelination. J Biol Chem 284:33692–33702CrossRefPubMedPubMedCentralGoogle Scholar
  29. Wang PS, Wang J, Zheng Y, Pallen CJ (2012) Loss of protein-tyrosine phosphatase alpha (PTPalpha) increases proliferation and delays maturation of oligodendrocyte progenitor cells. J Biol Chem 287(15):12529–12540CrossRefPubMedPubMedCentralGoogle Scholar
  30. Williams KE, Bundred NJ, Landberg G, Clarke RB, Farnie G (2015) Focal adhesion kinase and Wnt signaling regulate human ductal carcinoma in situ stem cell activity and response to radiotherapy. Stem Cells 33(2):327–341CrossRefPubMedGoogle Scholar
  31. Xie C, Li Z, Zhang GX, Guan Y (2014) Wnt signaling in remyelination in multiple sclerosis: friend or foe? Mol Neurobiol 49(3):1117–1125CrossRefPubMedGoogle Scholar
  32. Ye H, Zhao T, Tan YL, Liu J, Pallen CJ, Xiao ZC (2011) Receptor-like protein-tyrosine phosphatase alpha enhances cell surface expression of neural adhesion molecule NB-3. J Biol Chem 286(29):26071–26080CrossRefPubMedPubMedCentralGoogle Scholar
  33. Zeng L, D'Alessandri L, Kalousek MB, Vaughan L, Pallen CJ (1999) Protein tyrosine phosphatase alpha (PTPalpha) and contactin form a novel neuronal receptor complex linked to the intracellular tyrosine kinase fyn. J Cell Biol 147(4):707–714CrossRefPubMedPubMedCentralGoogle Scholar
  34. Zhang H, Jarjour AA, Boyd A, Williams A (2011) Central nervous system remyelination in culture—a tool for multiple sclerosis research. Exp Neurol 230(1):138–148CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Yuda Shih
    • 1
    • 2
    • 3
  • Philip T. T. Ly
    • 4
    • 2
    • 3
  • Jing Wang
    • 4
    • 3
  • Catherine J. Pallen
    • 1
    • 4
    • 2
    • 3
    Email author
  1. 1.Department of Pathology and Laboratory MedicineUniversity of British ColumbiaVancouverCanada
  2. 2.International Collaboration on Repair DiscoveriesUniversity of British ColumbiaVancouverCanada
  3. 3.BC Children’s Hospital Research InstituteUniversity of British ColumbiaVancouverCanada
  4. 4.Department of PediatricsUniversity of British ColumbiaVancouverCanada

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