Neurite outgrowth inhibitor Nogo-A establishes spatial segregation and extent of oligodendrocyte myelination

S. Y Christin Chong, Sheila S. Rosenberg, Stephen P J Fancy, Chao Zhao, Yun An A Shen, Angela T. Hahn, Aaron W. McGee, Xiaomei Xu, Binhai Zheng, Li I. Zhang, David H. Rowitch, Robin J M Franklin, Q. Richard Lu, Jonah R. Chan

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Abstract

A requisite component of nervous system development is the achievement of cellular recognition and spatial segregation through competition-based refinement mechanisms. Competition for available axon space by myelinating oligodendrocytes ensures that all relevant CNS axons are myelinated properly. To ascertain the nature of this competition, we generated a transgenic mouse with sparsely labeled oligodendrocytes and establish that individual oligodendrocytes occupying similar axon tracts can greatly vary the number and lengths of their myelin internodes. Here we show that intercellular interactions between competing oligodendroglia influence the number and length of myelin internodes, referred to as myelinogenic potential, and identify the amino-terminal region of Nogo-A, expressed by oligodendroglia, as necessary and sufficient to inhibit this process. Exuberant and expansive myelination/remyelination is detected in the absence of Nogo during development and after demyelination, suggesting that spatial segregation and myelin extent is limited by microenvironmental inhibition. We demonstrate a unique physiological role for Nogo-A in the precise myelination of the developing CNS. Maximizing the myelinogenic potential of oligodendrocytes may offer an effective strategy for repair in future therapies for demyelination.

Original languageEnglish (US)
Pages (from-to)1299-1304
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number4
DOIs
StatePublished - Jan 24 2012

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Chong, S. Y. C., Rosenberg, S. S., Fancy, S. P. J., Zhao, C., Shen, Y. A. A., Hahn, A. T., McGee, A. W., Xu, X., Zheng, B., Zhang, L. I., Rowitch, D. H., Franklin, R. J. M., Lu, Q. R., & Chan, J. R. (2012). Neurite outgrowth inhibitor Nogo-A establishes spatial segregation and extent of oligodendrocyte myelination. Proceedings of the National Academy of Sciences of the United States of America, 109(4), 1299-1304. https://doi.org/10.1073/pnas.1113540109