Demyelinating diseases of the central nervous system (CNS) are among the most devastating and disabling disorders that may arise during infancy through to adolescence and may lead to severe handicap and even death. A common feature of demyelinated lesions is the differentiation block of oligodendrocyte precursors (OPC) at a pre-myelinating stage. However, the mechanistic basis for inhibition of myelin repair is not fully understood. Our recent work together with others identified a Wnt/beta-catenin effector TCF7l2 as a new essential transcription factor for OPC differentiation. Activation of canonical Wnt signaling by stabilization of the ?-catenin/TCF complex was shown to inhibit oligodendrocyte differentiation. We further demonstrated that disruption of the ?-catenin/TCF7l2 interaction by HDAC1/2 reversed Wnt signaling inhibition and promoted oligodendrocyte differentiation, suggesting that TCF7l2 functions as a signaling integrator to control the timing of oligodendrocyte differentiation. The long-term objective of the research proposed here is to develop compounds that modulate the Wnt/TCF7l2 signaling to promote oligodendrocyte myelination and remyelination. We reason that surrogate targets for modulation of the Wnt/TCF7l2 activity might well be embedded within the TCF7l2 modifiers or downstream genetic targets. To understand the mechanism by which TCF7l2 controls oligodendrocyte differentiation and myelination in vivo, we will utilize floxed TCF7l2 mice that carry a cre-mediated conditional knockout mutation of TCF7l2 to examine the effect of loss of TCF7l2 on oligodendrocyte differentiation and TCF7l2 function at different developmental stages during oligodendrocyte development. In addition, we will use a combination of transcriptome-profiling and chromatin immunoprecipitation-sequencing approaches to identify TCF7l2 target genes on a genome-wide scale. These studies will provide new insights into the genetic program that TCF7l2 controls to mediate its effect on oligodendrocyte differentiation and myelination in the mammalian CNS. These studies will be crucial to our understating of the molecular basis of CNS myelination and suggest potential targets to Wnt/TCF signaling for treating patients with myelinating diseases such as multiple sclerosis and periventricular leukomalacia - a precursor lesion of cerebral palsy occurred in premature infants.

Public Health Relevance

The work proposed in research plans will provide better understanding of CNS myelination and offer new therapeutic strategies to enhance myelin repair. It will not only have scientific merits but also could be of practical value in treating adult patients with myelinating disorders such as multiple sclerosis and periventricular cerebral palsy, the common cause of severe disability in infants.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS072427-06
Application #
8733206
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Morris, Jill A
Project Start
2010-09-15
Project End
2015-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
He, Danyang; Wang, Jincheng; Lu, Yulan et al. (2017) lncRNA Functional Networks in Oligodendrocytes Reveal Stage-Specific Myelination Control by an lncOL1/Suz12 Complex in the CNS. Neuron 93:362-378
Weng, Qinjie; Wang, Jiajia; Wang, Jiaying et al. (2017) Folate Metabolism Regulates Oligodendrocyte Survival and Differentiation by Modulating AMPK? Activity. Sci Rep 7:1705
Wang, Haibo; Moyano, Ana Lis; Ma, Zhangyan et al. (2017) miR-219 Cooperates with miR-338 in Myelination and Promotes Myelin Repair in the CNS. Dev Cell 40:566-582.e5
Koreman, Elijah; Sun, Xiaowei; Lu, Q Richard (2017) Chromatin remodeling and epigenetic regulation of oligodendrocyte myelination and myelin repair. Mol Cell Neurosci :
Deng, Yaqi; Wu, Lai Man Natalie; Bai, Shujun et al. (2017) A reciprocal regulatory loop between TAZ/YAP and G-protein G?s regulates Schwann cell proliferation and myelination. Nat Commun 8:15161
Qu, Yi; Tang, Jun; Wang, Huiqing et al. (2017) RIPK3 interactions with MLKL and CaMKII mediate oligodendrocytes death in the developing brain. Cell Death Dis 8:e2629
Wu, Lai Man Natalie; Wang, Jincheng; Conidi, Andrea et al. (2016) Zeb2 recruits HDAC-NuRD to inhibit Notch and controls Schwann cell differentiation and remyelination. Nat Neurosci 19:1060-72
Steelman, Andrew J; Zhou, Yun; Koito, Hisami et al. (2016) Activation of oligodendroglial Stat3 is required for efficient remyelination. Neurobiol Dis 91:336-46
He, Danyang; Marie, Corentine; Zhao, Chuntao et al. (2016) Chd7 cooperates with Sox10 and regulates the onset of CNS myelination and remyelination. Nat Neurosci 19:678-689
Laitman, Benjamin M; Asp, Linnéa; Mariani, John N et al. (2016) The Transcriptional Activator Krüppel-like Factor-6 Is Required for CNS Myelination. PLoS Biol 14:e1002467

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