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Differential regulation of oligodendrocyte development and myelination by protein tyrosine phosphatase alpha and Wnt signaling Shih, Yuda


Oligodendrocytes (OLs) are the myelinating cells of the central nervous system (CNS). The myelination process is preceded by molecular and morphological differentiation of oligodendrocyte precursor cells (OPCs) into mature myelinating OLs. Protein tyrosince phosphatase alpha (PTPα) is a brain-enriched tyrosine phosphatase that regulates many cellular processes, including OPC differentiation. Our laboratory has previously demonstrated that PTPα null OPCs have impaired differentiation and brains of PTPα KO mice are hypomyelinated. In this study, I observed defective myelination in OL/neuron co-cultures where wild type (WT) and PTPα knock-out (KO) OPCs were introduced to neurite beds formed by dorsal root ganglion neurons for 14 days and immunostained for myelin basic protein (MBP), a component of the myelin sheath, and neurofilament (NFH), an axonal protein. MBP/NFH co-localization was used as an indicator of potential myelination. Co-localization is significantly reduced by ~50% in co-cultures with KO OPCs as compared to WT OPCs. Additionally, co-cultures with KO OPCs exhibit a reduced ability to form elongated MBP/NFH immunopositive segments, suggestive that in co-cultures with KO OPCs the ability to form elongated axo-glial contacts, a prerequisite for myelination, is impaired. This coincides with a reduction in MBP immunopositivity from ΚΟ OPCs, indicating a differentiation defect in the absence of PTPα. Pharmacological modulation of several signaling pathways has recently been shown to affect OL differentiation, myelination and remyelination. XAV939 is an inhibitor of canonical Wnt signaling and is known to promote OL differentiation and remyelination. Therefore, I investigated whether inhibition of Wnt signaling can remediate PTPα-dependent impairments in OL differentiation and myelination. I observed that inhibiting Wnt signaling can partially rescue PTPα-dependent impairments in differentiation; however, inhibition of Wnt signaling could not remediate the defects in elongation of MBP/NFH immunopositive segments in co-cultures with KO OPCs. While these studies reveal no apparent common molecular candidates between PTPα and Wnt signaling that may regulate OL differentiation, the findings described suggest that PTPα has at least two distinct roles during oligodendrocyte development: promoting OL differentiation by regulating MBP expression, formation and elongation of axo-glial contacts, both of which are prerequisite for myelination.

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