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The Journal of Neuroscience, September 9, 2009, 29(36):11304-11315; doi:10.1523/JNEUROSCI.1753-09.2009

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Cellular/Molecular
Sustained Axon–Glial Signaling Induces Schwann Cell Hyperproliferation, Remak Bundle Myelination, and Tumorigenesis

Jose A. Gomez-Sanchez,^1,3 Mikel Lopez de Armentia,² Rafael Lujan,⁴ Nicoletta Kessaris,⁵ William D. Richardson,⁵ and Hugo Cabedo^1,3

¹Biology of Myelin Diseases Laboratory and ²Synaptic Plasticity and Regulation of Gene Expression Laboratory, Instituto de Neurociencias de Alicante, Universitat Miguel Hernandez–Consejo Superior de Investigaciones Científicas, 03550 Sant Joan, Alicante, Spain, ³Unidad de Investigación del Hospital de Sant Joan, 03550 Sant Joan, Alicante, Spain, ⁴Centro Regional de Investigaciones Biomédicas, Universidad de Castilla-La Mancha, 02006 Albacete, Spain, and ⁵Wolfson Institute for Biomedical Research, University College London, WC1E 6BT London, United Kingdom

Correspondence should be addressed to Hugo Cabedo, Instituto de Neurociencias de Alicante Universitat Miguel Hernández–Consejo Superior de Investigaciones Científicas, Avda Santiago Ramon y Cajal sn, 03550 Sant Joan, Alicante, Spain. Email: hugo.cabedo{at}umh.es

Type III neuregulins exposed on axon surfaces control myelination of the peripheral nervous system. It has been shown, for example, that threshold levels of type III β1a neuregulin dictate not only the myelination fate of axons but also myelin thickness. Here we show that another neuregulin isoform, type III-β3, plays a distinct role in myelination. Neuronal overexpression of this isoform in mice stimulates Schwann cell proliferation and dramatically enlarges peripheral nerves and ganglia—which come to resemble plexiform neurofibromas—but have no effect on myelin thickness. The nerves display other neurofibroma-like properties, such as abundant collagen fibrils and abundant dissociated Schwann cells that in some cases produce big tumors. Moreover, the organization of Remak bundles is dramatically altered; the small-caliber axons of each bundle are no longer segregated from one another within the cytoplasm of a nonmyelinating Schwann cell but instead are close packed and the whole bundle wrapped as a single unit, frequently by a compact myelin sheath. Because Schwann cell hyperproliferation and Remak bundle degeneration are early hallmarks of type I neurofibromatosis, we suggest that sustained activation of the neuregulin pathway in Remak bundles can contribute to neurofibroma development.

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Received April 11, 2009; revised July 20, 2009; accepted July 28, 2009.

Correspondence should be addressed to Hugo Cabedo, Instituto de Neurociencias de Alicante Universitat Miguel Hernández–Consejo Superior de Investigaciones Científicas, Avda Santiago Ramon y Cajal sn, 03550 Sant Joan, Alicante, Spain. Email: hugo.cabedo{at}umh.es

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