Glial and Neuronal Protein Tyrosine Phosphatase Alpha (PTPα) Regulate Oligodendrocyte Differentiation and Myelination
- 348 Downloads
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.
KeywordsProtein 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.
- 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
- 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
- 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
- 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
- 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
- Maldonado PP, Angulo MC (2015) Multiple modes of communication between neurons and oligodendrocyte precursor cells. Neuroscientist 21(3):266–276Google Scholar
- 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