title: Dysregulation of the Wnt pathway inhibits timely myelination and remyelination in the mammalian CNS.
abstract: The progressive loss of CNS myelin in patients with multiple sclerosis (MS) has been proposed to result from the combined effects of damage to oligodendrocytes and failure of remyelination. A common feature of demyelinated lesions is the presence of oligodendrocyte precursors (OLPs) blocked at a premyelinating stage. However, the mechanistic basis for inhibition of myelin repair is incompletely understood. To identify novel regulators of OLP differentiation, potentially dysregulated during repair, we performed a genome-wide screen of 1040 transcription factor-encoding genes expressed in remyelinating rodent lesions. We report that approximately 50 transcription factor-encoding genes show dynamic expression during repair and that expression of the Wnt pathway mediator Tcf4 (aka Tcf7l2) within OLPs is specific to lesioned-but not normal-adult white matter. We report that beta-catenin signaling is active during oligodendrocyte development and remyelination in vivo. Moreover, we observed similar regulation of Tcf4 in the developing human CNS and lesions of MS. Data mining revealed elevated levels of Wnt pathway mRNA transcripts and proteins within MS lesions, indicating activation of the pathway in this pathological context. We show that dysregulation of Wnt-beta-catenin signaling in OLPs results in profound delay of both developmental myelination and remyelination, based on (1) conditional activation of beta-catenin in the oligodendrocyte lineage in vivo and (2) findings from APC(Min) mice, which lack one functional copy of the endogenous Wnt pathway inhibitor APC. Together, our findings indicate that dysregulated Wnt-beta-catenin signaling inhibits myelination/remyelination in the mammalian CNS. Evidence of Wnt pathway activity in human MS lesions suggests that its dysregulation might contribute to inefficient myelin repair in human neurological disorders.
authors.affiliation: Institute for Regeneration Medicine, Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, California 94143, USA.
authors.forename: Stephen P J
authors.initials: SP
authors.lastname: Fancy
authors.forename: Sergio E
authors.initials: SE
authors.lastname: Baranzini
authors.forename: Chao
authors.initials: C
authors.lastname: Zhao
authors.forename: Dong-In
authors.initials: DI
authors.lastname: Yuk
authors.forename: Karen-Amanda
authors.initials: KA
authors.lastname: Irvine
authors.forename: Sovann
authors.initials: S
authors.lastname: Kaing
authors.forename: Nader
authors.initials: N
authors.lastname: Sanai
authors.forename: Robin J M
authors.initials: RJ
authors.lastname: Franklin
authors.forename: David H
authors.initials: DH
authors.lastname: Rowitch
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002490:Central Nervous System / Q000254:growth & development* / Q000503:physiopathology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D009103:Multiple Sclerosis / Q000503:physiopathology*; D009186:Myelin Sheath / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000378:metabolism; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism* / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; D051820:TCF Transcription Factors; C532096:TCF4 protein, human; C090743:Tcf4 protein, mouse; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin