Myelin-producing oligodendrocytes play crucial roles in supporting development and neuronal function of the mammalian central nervous system (CNS). Multiple sclerosis, a devastating disease of the CNS is triggered directly or indirectly by the failure of oligodendrocyte remyelination and the degeneration of mature oligodendrocytes. Despite the enormous clinical impact of this demyelinating disease, the biological mechanisms that initiate myelinogenesis and those that cause this disease state are not well understood. In a previous screen for genes required for glial cell development, I cloned and characterized a pair of oligodendrocyte lineage genes (Olig1/2) that encode a novel class of basic helix-loop-helix transcription factors. The Olig1 gene is expressed in oligodendrocyte progenitor cells and mature oligodendrocytes in rodents. Olig2 is essential for the formation of oligodendrocytes and motor neurons in the developing spinal cord. Gain-of-function and loss-of-function genetic studies show that Olig2 gene is critical for mediating oligodendrocyte development. The research proposal described here builds upon these preliminary studies. I will use in vivo conditional mutagenesis approaches to dissect the biological and pathological functions of the Olig2 gene in oligodendrocyte myelination and remyelination in an injury-induced demyelinating animal model. These studies should contribute significantly to our understanding of the molecular mechanisms of oligodendrocyte myelination and remyelination, and will offer new avenues for diagnosis and treatment of demyelinating diseases such as multiple sclerosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS050389-02
Application #
7070562
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Utz, Ursula
Project Start
2005-07-01
Project End
2010-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
2
Fiscal Year
2006
Total Cost
$352,273
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
He, Li; Lu, Q Richard (2013) Coordinated control of oligodendrocyte development by extrinsic and intrinsic signaling cues. Neurosci Bull 29:129-43
He, Xuelian; Yu, Yang; Awatramani, Rajeshwar et al. (2012) Unwrapping myelination by microRNAs. Neuroscientist 18:45-55
Zhao, Xianghui; He, Xuelian; Han, Xiaolei et al. (2010) MicroRNA-mediated control of oligodendrocyte differentiation. Neuron 65:612-26
Yu, Yang; Casaccia, Patrizia; Lu, Q Richard (2010) Shaping the oligodendrocyte identity by epigenetic control. Epigenetics 5:124-8
Ye, Feng; Chen, Ying; Hoang, ThaoNguyen et al. (2009) HDAC1 and HDAC2 regulate oligodendrocyte differentiation by disrupting the beta-catenin-TCF interaction. Nat Neurosci 12:829-38
Chen, Ying; Wu, Heng; Wang, Shuzong et al. (2009) The oligodendrocyte-specific G protein-coupled receptor GPR17 is a cell-intrinsic timer of myelination. Nat Neurosci 12:1398-406
Zhang, Yueting; Argaw, Azeb Tadesse; Gurfein, Blake T et al. (2009) Notch1 signaling plays a role in regulating precursor differentiation during CNS remyelination. Proc Natl Acad Sci U S A 106:19162-7
Chen, Ying; Miles, Darryl K; Hoang, Thaonguyen et al. (2008) The basic helix-loop-helix transcription factor olig2 is critical for reactive astrocyte proliferation after cortical injury. J Neurosci 28:10983-9
Chen, Ying; Balasubramaniyan, Veerakumar; Peng, Jie et al. (2007) Isolation and culture of rat and mouse oligodendrocyte precursor cells. Nat Protoc 2:1044-51
Cai, Jeff; Chen, Ying; Cai, Wen-Hui et al. (2007) A crucial role for Olig2 in white matter astrocyte development. Development 134:1887-99

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