? Homeostatic regulation of NG2 cell dynamics NG2 cells represent a fourth major glial cell population in the mammalian central nervous system that is distinct from neural stem cells, mature oligodendrocytes, astrocytes, or microglia. They generate oligodendrocytes and hence are an important source of remyelinating cells. They respond robustly to changes in the density of oligodendrocyte lineage cells or myelin and restore the correct number of oligodendrocytes needed to make the correct amount of myelin in the neural network. They are highly integrated in the neural network and interact not only among the cells in the oligodendrocyte lineage but also with neurons and other glia. The proposed project will investigate the mechanism of feedback signaling that maintains homeostasis of oligodendrocytes and myelin.
In Aim 1, we will test the hypothesis that microglia play a critical role in regulating NG2 cell density under normal physiological conditions, as well as during remyelination.
In Aim 2, we will test the hypotheses that the Hippo signaling mediates NG2 cell density-dependent proliferation and that cell adhesion molecules and exosome signaling between myelin and NG2 cells provide feedback signaling to NG2 cells that regulates oligodendrocyte differentiation. These hypotheses are based on findings from both systems analyses and specific cellular studies. The outcome of the study will advance our knowledge by establishing fundamental new principles related to oligodendrocyte lineage cell intrinsic and extrinsic mechanisms of homeostatic regulation of oligodendrocytes and myelin in the context of other cellular constituents.

Public Health Relevance

NG2 cells represent a major glial cell population in the mammalian brain that is distinct from other cell types. They provide an important source of oligodendrocytes for myelin maintenance and repair. NG2 cells are highly integrated in the neural network and respond to changes in oligodendrocyte lineage cell and myelin density. In this project, the nature of the signaling between NG2 cells and other cell types that affect NG2 cell proliferation and differentiation will be explored. Results from these studies can be used to develop new context-dependent strategies to harness NG2 cells for the repair of demyelinated lesions.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Cellular and Molecular Biology of Glia Study Section (CMBG)
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Utz, Ursula
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University of Connecticut
Schools of Arts and Sciences
United States
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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
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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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