Fancy SP, Baranzini SE, Zhao C, Yuk DI, Irvine KA, Kaing S et al. Dysregulation of the Wnt pathway inhibits timely myelination and remyelination in the mammalian CNS. Genes Dev 23: 1571-1585

Institute for Regeneration Medicine, Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, California 94143, USA.
Genes & development (Impact Factor: 10.8). 07/2009; 23(13):1571-85. DOI: 10.1101/gad.1806309
Source: PubMed


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.

Download full-text


Available from: Sergio E Baranzini
  • Source
    • "OPCs maintain their selfrenewal capability through tonic activation of β-catenin, a key Wnt pathway intermediate (Fancy et al., 2009). β-catenin activation delays the differentiation and myelination of OPCs (Fancy et al., 2009). Recent evidence demonstrates that this tonic activation of β-catenin is partially mediated through the tonic inhibition of RPTPβ by its inhibitory ligand pleiotrophin (McClain et al., 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Chondroitin Sulfate Proteoglycans (CSPGs) are a major component of the extracellular matrix in the central nervous system (CNS) and play critical role in the development and pathophysiology of the brain and spinal cord. Developmentally, CSPGs provide guidance cues for growth cones and contribute to the formation of neuronal boundaries in the developing CNS. Their presence in perineuronal nets plays a crucial role in the maturation of synapses and closure of critical periods by limiting synaptic plasticity. Following injury to the CNS, CSPGs are dramatically upregulated by reactive glia which form a glial scar around the lesion site. Increased level of CSPGs is a hallmark of all CNS injuries and has been shown to limit axonal plasticity, regeneration, remyelination, and conduction after injury. Additionally, CSPGs create a non-permissive milieu for cell replacement activities by limiting cell migration, survival and differentiation. Mounting evidence is currently shedding light on the potential benefits of manipulating CSPGs in combination with other therapeutic strategies to promote spinal cord repair and regeneration. Moreover, the recent discovery of multiple receptors for CSPGs provides new therapeutic targets for targeted interventions in blocking the inhibitory properties of CSPGs following injury. Here, we will provide an in depth discussion on the impact of CSPGs in normal and pathological CNS. We will also review the recent preclinical therapies that have been developed to target CSPGs in the injured CNS. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Apr 2015 · Experimental Neurology
  • Source
    • "Shh and Sox17 have both been identified as positive regulators of oligodendrogenesis and remyelination (Ferent et al., 2013; Ming et al., 2013), and Shh transcripts are detected only in OPCs engaged in remyelination (Ferent et al., 2013). Musashi1 (Msi1), Myt1, Tcf4 (Tcf7l2) and Nkx2.2 are expressed in OPCs in white matter regions during development, and their expression is upregulated in OPCs after demyelination (Dobson et al., 2008; Fancy et al., 2004, 2009; Sim et al., 2002; Vana et al., 2007; Watanabe et al., 2004). Furthermore, although Olig2-expressing progenitors appear to be a major cell population involved in remyelination (Aguirre et al., 2007; Fancy et al., 2004; Menn et al., 2006), maintenance of nuclear Olig2 expression is required for oligodendrocyte regeneration, as translocation of Olig2 from the nucleus to the cytoplasm is associated with induction of GFAP expression and astrogliogenesis (Cassiani-Ingoni et al., 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Amongst neurological diseases, multiple sclerosis (MS) presents an attractive target for regenerative medicine. This is because the primary pathology, the loss of myelin-forming oligodendrocytes, can be followed by a spontaneous and efficient regenerative process called remyelination. While cell transplantation approaches have been explored as a means of replacing lost oligodendrocytes, more recently therapeutic approaches that target the endogenous regenerative process have been favored. This is in large part due to our increasing understanding of (1) the cell types within the adult brain that are able to generate new oligodendrocytes, (2) the mechanisms and pathways by which this achieved, and (3) an emerging awareness of the reasons why remyelination efficiency eventually fails. Here we review some of these advances and also highlight areas where questions remain to be answered in both the biology and translational potential of this important regenerative process. GLIA 2014;
    Preview · Article · Nov 2014 · Glia
  • Source
    • "sFRP3 is a soluble decoy receptor that modulate Wntsignaling (Jones and Jomary, 2002). It was not included in our previous study (Holmoy et al., 2013), but was now incorporated as recent studies have shown that Wnt-signaling is upregulated in lesions in both MS models and patients (Fancy et al., 2009), where it may inhibit oligodendrocyte maturation and remyelination (Hanafy and Sloane, 2011). Table 2 Change in inflammation marker levels with each SD-increase of vitamin levels during the whole study period. "
    [Show abstract] [Hide abstract]
    ABSTRACT: To explore the relationships between vitamin A, D and E and inflammation in relapsing remitting multiple sclerosis, we assessed their associations with 11 inflammation markers in 9 serial serum samples from 85 patients, before and during interferon-β1a treatment. A negative association was found between vitamin A and pentraxin 3 independent of interferon-β1a use, whereas positive associations between vitamin D and interleukin-1 receptor antagonist and secreted frizzled-related protein 3 were seen before, and between vitamin E and chemokine (C-X-C motif) ligand 16 during interferon-β1a treatment. These findings suggest associations with diverse inflammatory pathways, which may be differentially influenced by interferon-β1a treatment.
    Full-text · Article · Jun 2014 · Journal of neuroimmunology
Show more