? 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS073425-07
Application #
9419318
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Utz, Ursula
Project Start
2011-06-15
Project End
2022-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
7
Fiscal Year
2018
Total Cost
Indirect Cost
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
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; 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
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; Medved, Jelena et al. (2013) NG2 cells in white matter but not gray matter proliferate in response to PDGF. J Neurosci 33:14558-66
Zuo, Hao; Nishiyama, Akiko (2013) Polydendrocytes in development and myelin repair. Neurosci Bull 29:165-76
Kim, Youngmi; Kim, Eunhee; Wu, Qiulian et al. (2012) Platelet-derived growth factor receptors differentially inform intertumoral and intratumoral heterogeneity. Genes Dev 26:1247-62
Zhu, Xiaoqin; Zuo, Hao; Maher, Brady J et al. (2012) Olig2-dependent developmental fate switch of NG2 cells. Development 139:2299-307