Multiple sclerosis (MS) is a demyelinating disease that affects 350,000 people in the U.S. and is a major cause of chronic neurological deficit, affecting adults during their most active period of their lives. Remyelination failure is a characteristic of long-standing and primary progressive lesions of MS and is associated with impulse conduction failure and axonal pathology. Despite the debilitating clinical effects of remyelination failure, the reason why some lesions are effectively remyelinated while others are not remains unclear. Glial cells that express the NG2 proteoglycan (NG2 cells) exist widely throughout the mature central nervous system. Recent genetic fate mapping studies have provided direct demonstration that they generate oligodendrocytes not only during development but also in the mature central nervous system. Using new transgenic mouse lines that we have generated, we have observed that deletion of the basic helix-loop-helix transcription factor Olig2 specifically in mature NG2 cells reduces the number of oligodendrocytes that are produced from NG2 cells in the adult brain. We have also performed a high throughput screen to identify compounds that upregulate Olig2 transcription. We will use these newly acquired tools to test the hypothesis that a critical level of Olig2 is required for successful remyelination in experimental autoimmune encephalomyelitis (EAE), which is a clinically relevant rodent model of MS. This will be tested in the following three specific aims.
In Aim 1, we will determine whether loss of Olig2 will compromise the ability of NG2 cells to produce new oligodendrocytes in EAE lesions.
In Aim 2, we will determine whether the newly identified compounds that increase Olig2 transcription activate the Sonic hedgehog-Gli pathway or the mitogen-activated protein kinase pathway and test compounds that affect different pathways for their ability to promote remyelination in EAE.
In Aim 3, we will determine whether loss of Ezh2, which is a member of the Polycomb Repressor Complex responsible for methylating lysine 27 on histone H3, will promote remyelination by derepressing genes required for myelination.

Public Health Relevance

This application will investigate mechanisms that determine the extent of remyelination of demyelinated lesions in a clinically relevant rodent model of multiple sclerosis. Newly generated transgenic mice will be used to investigate the extent of remyelination by pharmacologically and genetically modulating a key transcription factor that is important for oligodendrocyte differentiation. The outcome of these studies may be used to design new therapeutic strategies for stimulating endogenous progenitor cells to repair demyelinated lesions in multiple sclerosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS073425-03
Application #
8471798
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Utz, Ursula
Project Start
2011-06-15
Project End
2016-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
3
Fiscal Year
2013
Total Cost
$316,596
Indirect Cost
$105,502
Name
University of Connecticut
Department
Physiology
Type
Schools of Arts and Sciences
DUNS #
614209054
City
Storrs-Mansfield
State
CT
Country
United States
Zip Code
06269
Hesp, Zoe C; Yoseph, Rim Y; Suzuki, Ryusuke et al. (2018) Proliferating NG2-Cell-Dependent Angiogenesis and Scar Formation Alter Axon Growth and Functional Recovery After Spinal Cord Injury in Mice. J Neurosci 38:1366-1382
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
Sherafat, Amin; Hill, Robert A; Nishiyama, Akiko (2018) Organotypic Slice Cultures to Study Oligodendrocyte Proliferation, Fate, and Myelination. Methods Mol Biol 1791:145-156
Gotoh, Hitoshi; Wood, William M; Patel, Kiran D et al. (2018) NG2 expression in NG2 glia is regulated by binding of SoxE and bHLH transcription factors to a Cspg4 intronic enhancer. Glia 66:2684-2699
Serwanski, David R; Jukkola, Peter; Nishiyama, Akiko (2017) Heterogeneity of astrocyte and NG2 cell insertion at the node of ranvier. J Comp Neurol 525:535-552
Nishiyama, Akiko; Boshans, Linda; Goncalves, Christopher M et al. (2016) Lineage, fate, and fate potential of NG2-glia. Brain Res 1638:116-128
Nishiyama, Akiko; Suzuki, Ryusuke; Zhu, Xiaoqin (2014) NG2 cells (polydendrocytes) in brain physiology and repair. Front Neurosci 8:133
Hill, Robert A; Nishiyama, Akiko (2014) NG2 cells (polydendrocytes): listeners to the neural network with diverse properties. Glia 62:1195-210
Hill, Robert A; Patel, Kiran D; Goncalves, Christopher M et al. (2014) Modulation of oligodendrocyte generation during a critical temporal window after NG2 cell division. Nat Neurosci 17:1518-27
Hill, Robert A; Medved, Jelena; Patel, Kiran D et al. (2014) Organotypic slice cultures to study oligodendrocyte dynamics and myelination. J Vis Exp :e51835

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