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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Morris, Jill A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
Schools of Medicine
San Francisco
United States
Zip Code
Shen, Yun-An A; Chen, Yan; Dao, Dang Q et al. (2014) Phosphorylation of LKB1/Par-4 establishes Schwann cell polarity to initiate and control myelin extent. Nat Commun 5:4991
Mei, Feng; Christin Chong, S Y; Chan, Jonah R (2013) Myelin-based inhibitors of oligodendrocyte myelination: clues from axonal growth and regeneration. Neurosci Bull 29:177-88
Lee, Seonok; Chong, S Y Christin; Tuck, Samuel J et al. (2013) A rapid and reproducible assay for modeling myelination by oligodendrocytes using engineered nanofibers. Nat Protoc 8:771-82
Mei, Feng; Wang, Hongkai; Liu, Shubao et al. (2013) Stage-specific deletion of Olig2 conveys opposing functions on differentiation and maturation of oligodendrocytes. J Neurosci 33:8454-62
Chong, S Y Christin; Rosenberg, Sheila S; Fancy, Stephen P J et al. (2012) Neurite outgrowth inhibitor Nogo-A establishes spatial segregation and extent of oligodendrocyte myelination. Proc Natl Acad Sci U S A 109:1299-304
Tep, Chhavy; Kim, Mi Lyang; Opincariu, Laura I et al. (2012) Brain-derived neurotrophic factor (BDNF) induces polarized signaling of small GTPase (Rac1) protein at the onset of Schwann cell myelination through partitioning-defective 3 (Par3) protein. J Biol Chem 287:1600-8
Redmond, Stephanie A; Chan, Jonah R (2012) Neuroscience. Revitalizing remyelination--the answer is circulating. Science 336:161-2
Lewallen, Kathryn A; Shen, Yun-An A; De la Torre, Asia R et al. (2011) Assessing the role of the cadherin/catenin complex at the Schwann cell-axon interface and in the initiation of myelination. J Neurosci 31:3032-43
Chong, S Y Christin; Chan, Jonah R (2010) Tapping into the glial reservoir: cells committed to remaining uncommitted. J Cell Biol 188:305-12
Rosenberg, Sheila S; Chan, Jonah R (2009) Modulating myelination: knowing when to say Wnt. Genes Dev 23:1487-93