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.
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.
|Zheng, Zhen; Zhang, Li; Qu, Yi et al. (2018) Mesenchymal Stem Cells Protect Against Hypoxia-Ischemia Brain Damage by Enhancing Autophagy Through Brain Derived Neurotrophic Factor/Mammalin Target of Rapamycin Signaling Pathway. Stem Cells :|
|Zhao, Chuntao; Dong, Chen; Frah, Magali et al. (2018) Dual Requirement of CHD8 for Chromatin Landscape Establishment and Histone Methyltransferase Recruitment to Promote CNS Myelination and Repair. Dev Cell 45:753-768.e8|
|Weng, Qinjie; Wang, Jiaying; Wang, Jiajia et al. (2018) Lenalidomide regulates CNS autoimmunity by promoting M2 macrophages polarization. Cell Death Dis 9:251|
|Lu, Xu-Feng; Cao, Xiao-Yue; Zhu, Yong-Jie et al. (2018) Histone deacetylase 3 promotes liver regeneration and liver cancer cells proliferation through signal transducer and activator of transcription 3 signaling pathway. Cell Death Dis 9:398|
|He, Xuelian; Zhang, Liguo; Queme, Luis F et al. (2018) A histone deacetylase 3-dependent pathway delimits peripheral myelin growth and functional regeneration. Nat Med 24:338-351|
|Zuo, Hao; Wood, William M; Sherafat, Amin et al. (2018) Age-Dependent Decline in Fate Switch from NG2 Cells to Astrocytes After Olig2 Deletion. J Neurosci 38:2359-2371|
|Jiang, Minqing; Rao, Rohit; Wang, Jincheng et al. (2018) The TSC1-mTOR-PLK axis regulates the homeostatic switch from Schwann cell proliferation to myelination in a stage-specific manner. Glia 66:1947-1959|
|Wu, Lai Man Natalie; Deng, Yaqi; Wang, Jincheng et al. (2018) Programming of Schwann Cells by Lats1/2-TAZ/YAP Signaling Drives Malignant Peripheral Nerve Sheath Tumorigenesis. Cancer Cell 33:292-308.e7|
|Merten, Nicole; Fischer, Julia; Simon, Katharina et al. (2018) Repurposing HAMI3379 to Block GPR17 and Promote Rodent and Human Oligodendrocyte Differentiation. Cell Chem Biol 25:775-786.e5|
|Gregath, Alexander; Lu, Qing Richard (2018) Epigenetic modifications-insight into oligodendrocyte lineage progression, regeneration, and disease. FEBS Lett 592:1063-1078|
Showing the most recent 10 out of 58 publications