The long-term goal of this study is to understand the molecular mechanisms that control the specification and differentiation of oligodendrocytes. Although considerable insights have been gained into the molecular mechanisms that control the initial specification of oligodendrocytes, it is still not clear how the terminal differentiation and myelination of oligodendrocytes are regulated during animal development. Recently, we have demonstrated that oligodendrocyte progenitor cells start to acquire the expression of Nkx2.2 homeodomain transcription factor during their migration to their destination sites, and expression of Nkx2.2 is required for oligodendrocyte differentiation and myelin gene expression. Here we hypothesize that Nkx2.2 plays a key role in controlling the timing of oligodendrocyte differentiation and myelination during animal development, and the expression and activity of Nkx2.2 are tightly regulated by both intracellular and extracellular factors.
Specific aim 1 of this proposal is to test the hypothesis that Nkx2.2 and Sox10 interact physically and have synergistic actions on activating myelin gene expression and oligodendrocyte differentiation.
Specific aim 2 is to test the hypothesis that Nkx2.2 expression in oligodendrocyte progenitor cells can be induced by extracellular factors (thyroid hormone) that promote oligodendrocyte differentiation.
Specific aim 3 is to test the hypothesis that the Notch pathway controls the timing of oligodendrocyte differentiation by regulating Nkx2.2 expression in oligodendrocyte progenitor cells.
Specific aim 4 is to test the hypothesis that Nkx2.2 regulates oligodendrocyte myelination at later stages of animal life in collaboration with Nkx6.2. Results derived from the proposed studies will significantly enhance our understanding of the genetic circuitry governing the early specification and differentiation of oligodendrocytes, and may provide theoretic basis for design of novel therapeutic approaches for prevention and treatment of motor neuron and oligodendrocyte atrophies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS037717-05
Application #
6733111
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Utz, Ursula
Project Start
2000-03-01
Project End
2008-02-28
Budget Start
2004-03-01
Budget End
2005-02-28
Support Year
5
Fiscal Year
2004
Total Cost
$305,251
Indirect Cost
Name
University of Louisville
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
Zhu, Q; Tan, Z; Zhao, S et al. (2015) Developmental expression and function analysis of protein tyrosine phosphatase receptor type D in oligodendrocyte myelination. Neuroscience 308:106-14
Zhu, Qiang; Zhao, Xiaofeng; Zheng, Kang et al. (2014) Genetic evidence that Nkx2.2 and Pdgfra are major determinants of the timing of oligodendrocyte differentiation in the developing CNS. Development 141:548-55
Zhao, X; Huang, H; Chen, Y et al. (2013) Dynamic expression of secreted Frizzled-related protein 3 (sFRP3) in the developing mouse spinal cord and dorsal root ganglia. Neuroscience 248:594-601
Du, E; Li, Hong; Jin, Shunying et al. (2013) Evidence that TMEM67 causes polycystic kidney disease through activation of JNK/ERK-dependent pathways. Cell Biol Int 37:694-702
Zhu, Ying; Li, Hong; Li, Kehan et al. (2013) Necl-4/SynCAM-4 is expressed in myelinating oligodendrocytes but not required for axonal myelination. PLoS One 8:e64264
Huang, Hao; Zhao, Xiao-Feng; Zheng, Kang et al. (2013) Regulation of the timing of oligodendrocyte differentiation: mechanisms and perspectives. Neurosci Bull 29:155-64
Zheng, Kang; Li, Hong; Huang, Hao et al. (2012) MicroRNAs and glial cell development. Neuroscientist 18:114-8
Zheng, Kang; Li, Hong; Zhu, Ying et al. (2010) MicroRNAs are essential for the developmental switch from neurogenesis to gliogenesis in the developing spinal cord. J Neurosci 30:8245-50
Zhu, Ying; Park, Jinsil; Hu, Xuemei et al. (2010) Control of oligodendrocyte generation and proliferation by Shp2 protein tyrosine phosphatase. Glia 58:1407-14
Cai, Jun; Zhu, Qiang; Zheng, Kang et al. (2010) Co-localization of Nkx6.2 and Nkx2.2 homeodomain proteins in differentiated myelinating oligodendrocytes. Glia 58:458-68

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