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 ;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 b-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-b-catenin signaling in OLPs results in profound delay of both developmental myelination and remyelination, based on (1) conditional activation of b-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-b-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.[Keywords: Oligodendrocyte; CNS development; Wnt; multiple sclerosis; remyelination; Olig2] Supplemental material is available at http://www.genesdev.org.

Cell Therapy for Multiple Sclerosis

“…Analysis of gene expression profiles during development in the normal adult brain and during demyelination identified several novel regulatory pathways of oligodendrocyte differentiation. These studies showed that oligodendrocyte differentiation and remyelination are dependent on retinoid-X receptor-gamma receptor agonists [115] and on Wnt-beta-catenin signaling [116]. In addition, type 2 cyclin dependent kinase (also known as cdk2), which controls the cell cycle, does not interfere with myelination during development, but its knock-out facilitates remyelination [117].…”

Myelin Regeneration in Multiple Sclerosis: Targeting Endogenous Stem Cells

“…A screen for transcription factors associated with CNS remyelination in experimentally demyelinated mice led to the identification of Tcf4 expression in oligodendrocyte lineage cells and the elucidation of the canonical Wnt pathway as a negative regulator of precursor differentiation [55]. Tcf4 is expressed in the mouse white matter immediately after birth, but it is barely detectable in the adult [55][56][57].…”

“…Tcf4 is expressed in the mouse white matter immediately after birth, but it is barely detectable in the adult [55][56][57]. However, following CNS injury, Tcf4 is reexpressed and upregulated in OPCs that are recruited to the lesion [56].…”

“…In response to Wnt activation, Tcf4 is thought to interact with β-catenin in the nucleus to regulate transcription of Wnt-β-catenin pathway target genes [58]. Indeed, disruption of Wnt signaling in oligodendrocyte lineage cells by using transgenic mice that actively express a dominant active β-catenin gene results in mice displaying severe tremor and ataxia within 1 week after birth due to delayed oligodendrocyte differentiation and hypomyelination [55]. However, this effect is transient as CNS myelination ultimately catches up and appears normal in adult mice.…”

Dose-dependent regulation of oligodendrocyte specification by β-catenin signaling

“…For instance, the ΔExon3 mutation of β-catenin [1][2][3][4] , which stabilizes β-catenin by deletion …”