Cell polarity is critical for various cellular processes including establishing the antero-posterior axis, generating distinct membrane specializations (apical and basal polarity), as well as asymmetric cell division and axon specification. Essentially, cell polarity plays fundamental roles in helping to organize and integrate complex molecular signals in order for cells to make decisions concerning fate, orientation, differentiation, and interaction. In the nervous system, neurons and glia share a mutual dependence in establishing a functional relationship, and none is more evident than the process by which glia form myelin around axons. The formation of myelin is an exquisite example of cell-cell interaction, which consists of the polarized or unidirectional wrapping of multiple layers of membrane concentrically around an axon initiated at the site of the axon-glial interface. While myelination is a highly polarized process, the involvement of cell polarity in its formation remain largely uncharacterized. We have recently identified a novel role for the Par (partitioning defective) polarity complex in the initiation of myelination. This polarity complex localizes asymmetrically in myelin- forming cells at the SC-axon interface, and disruption of Par localization, dramatically inhibits myelination without affecting cell division, migration, or even axonal alignment. The central hypothesis of this proposal is that axonal signals facilitate the breaking of symmetry in the SC and initiate myelination by coordinating cytoskeletal dynamics/rearrangement and gene expression. Our recent findings provide us with a rare opportunity to characterize the presence of this polarized molecular scaffold at the SC-axon interface that leads to the unidirectional activation of myelination. A clear understanding of the molecular and cellular events that pave the way for the myelin-forming cell is vital in advancing therapies for demyelinating diseases such as Multiple Sclerosis, the peripheral neuropathies, and even nerve injury.

Public Health Relevance

Myelination is an exquisite and dynamic example of cell-cell interaction, which requires a series of highly orchestrated events that balance both extrinsic and intrinsic mechanisms to coordinate the spatiotemporal regulation. Demyelination as a result of disease or injury severely disrupts the efficient transmission of the action potential, ultimately resulting in a loss of function. In order to effectively treat these devastating conditions, it is essential to expand our knowledge concerning the generation and maturation of the myelin- forming cells and the processes that lead to myelination.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS062796-10
Application #
9270077
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Morris, Jill A
Project Start
2008-07-15
Project End
2019-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
10
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Neurology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
Osso, Lindsay A; Chan, Jonah R (2017) Architecting the myelin landscape. Curr Opin Neurobiol 47:1-7
Petersen, Mark A; Ryu, Jae Kyu; Chang, Kae-Jiun et al. (2017) Fibrinogen Activates BMP Signaling in Oligodendrocyte Progenitor Cells and Inhibits Remyelination after Vascular Damage. Neuron 96:1003-1012.e7
Pan, Simon; Chan, Jonah R (2017) Regulation and dysregulation of axon infrastructure by myelinating glia. J Cell Biol 216:3903-3916
Wu, Lai Man Natalie; Wang, Jincheng; Conidi, Andrea et al. (2016) Zeb2 recruits HDAC-NuRD to inhibit Notch and controls Schwann cell differentiation and remyelination. Nat Neurosci 19:1060-72
Mei, Feng; Mayoral, Sonia R; Nobuta, Hiroko et al. (2016) Identification of the Kappa-Opioid Receptor as a Therapeutic Target for Oligodendrocyte Remyelination. J Neurosci 36:7925-35
Chang, Kae-Jiun; Redmond, Stephanie A; Chan, Jonah R (2016) Remodeling myelination: implications for mechanisms of neural plasticity. Nat Neurosci 19:190-7
Mei, Feng; Lehmann-Horn, Klaus; Shen, Yun-An A et al. (2016) Accelerated remyelination during inflammatory demyelination prevents axonal loss and improves functional recovery. Elife 5:
Mayoral, Sonia R; Chan, Jonah R (2016) The environment rules: spatiotemporal regulation of oligodendrocyte differentiation. Curr Opin Neurobiol 39:47-52
Etxeberria, Ainhoa; Hokanson, Kenton C; Dao, Dang Q et al. (2016) Dynamic Modulation of Myelination in Response to Visual Stimuli Alters Optic Nerve Conduction Velocity. J Neurosci 36:6937-48
Redmond, Stephanie A; Mei, Feng; Eshed-Eisenbach, Yael et al. (2016) Somatodendritic Expression of JAM2 Inhibits Oligodendrocyte Myelination. Neuron 91:824-836

Showing the most recent 10 out of 27 publications