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A functional role for EGFR signaling in myelination and remyelination

Nature Neuroscience volume 10, pages 990–1002 (2007)Cite this article

Abstract

Cellular strategies for oligodendrocyte regeneration and remyelination involve characterizing endogenous neural progenitors that are capable of generating oligodendrocytes during normal development and after demyelination, and identifying the molecular signals that enhance oligodendrogenesis from these progenitors. Using both gain- and loss-of-function approaches, we explored the role of epidermal growth factor receptor (EGFR) signaling in adult myelin repair and in oligodendrogenesis. We show that 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNP) promoter–driven overexpression of human EGFR (hEGFR) accelerated remyelination and functional recovery following focal demyelination of mouse corpus callosum. Lesion repopulation by Cspg4+ (also known as NG2) Ascl1+ (also known as Mash1) Olig2+ progenitors and functional remyelination were accelerated in CNP-hEGFR mice compared with wild-type mice. EGFR overexpression in subventricular zone (SVZ) and corpus callosum during early postnatal development also expanded this NG2+Mash1+Olig2+ progenitor population and promoted SVZ-to-lesion migration, enhancing oligodendrocyte generation and axonal myelination. Analysis of hypomorphic EGFR-mutant mice confirmed that EGFR signaling regulates oligodendrogenesis and remyelination by NG2+Mash1+Olig2+ progenitors. EGFR targeting holds promise for enhancing oligodendrocyte regeneration and myelin repair.

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Figure 1: EGFR overexpression enhances NG2+Olig2+Mash1+ progenitor cell proliferation in corpus callosum after focal demyelination.
Figure 2: EGFR overexpression enhances oligodendrogenesis and remyelination after focal demyelination.
Figure 3: EGFR overexpression enhances axonal remyelination after focal demyelination.
Figure 4: Reduced EGFR signaling impairs proliferation of NG2+Olig2+Mash1+ progenitor cells and corpus callosum remyelination after focal demyelination.
Figure 5: EGFR overexpression enhances oligodendrogenesis and myelination during development.
Figure 6: Reduced EGFR signaling decreases the number of NG2+Mash1+Olig2+ progenitors and oligodendrocytes in the corpus callosum.
Figure 7: EGFR overexpression enhances NG2+ cell proliferation and expands the NG2+Mash1+Olig2+ progenitor population in the postnatal SVZ.
Figure 8: EGFR overexpression enhances NG2+Olig2+Mash1+ progenitor cell recruitment to the demyelinated lesion.

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Acknowledgements

We thank N. Ratner for the CNP-hEGFR mice, for encouragement and for valuable discussion. We thank F. Gage and J. Goldman for the gift of pNIT-GFP retrovirus, and D. Rowitch for the gift of anti-Olig1 and anti-Olig2 antibodies. We thank R. Armstrong and L.-J. Chew for their comments on this manuscript. We are particularly grateful to J. Corbin for discussion and for critically reading several versions of this manuscript. We also thank S. Temple, T. Haydar and B. Jablonska for their comments on an earlier version of the manuscript. We thank A. Baron-Van Evercooren for technical advice on the focal demyelination model and for discussion. We thank D. Bergles for technical advice on the experiments on compound action potentials. This work was supported by US National Institutes of Health R01NS045702 (V.G.), R21NS050463 (V.G.), and by US National Institutes of Health MRDDRC P30HD40677. Electron microscopy was performed at the Virginia Commonwealth University, Department of Neurobiology and Anatomy Microscopy Facility, supported, in part, with funding from US National Institutes of Health Center Core Grant 5P30NS047463.

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Authors and Affiliations

  1. Center for Neuroscience Research, Children's National Medical Center, 111 Michigan Ave., NW, Washington, 20010-2970, DC, USA

    Adan Aguirre, J M Mangin & Vittorio Gallo

  2. Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Campus, Box 980709, Richmond, 23298-0709, VA, USA

    Jeff L Dupree

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Contributions

A.A. conducted all the experiments, except for the electrophysiology and electron microscopy, and wrote the manuscript together with V.G. J.L.D. performed the electron microscopy analysis, J.M.M. conducted the electrophysiology experiments and V.G. supervised the project and wrote the manuscript with A.A.

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Correspondence to Vittorio Gallo.

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Aguirre, A., Dupree, J., Mangin, J. et al. A functional role for EGFR signaling in myelination and remyelination. Nat Neurosci 10, 990–1002 (2007). https://doi.org/10.1038/nn1938

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