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The Journal of Neuroscience, March 22, 2006, 26(12):3079-3086; doi:10.1523/JNEUROSCI.3785-05.2006

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Cellular/Molecular
Neuregulin 1–erbB Signaling Is Necessary for Normal Myelination and Sensory Function

Suzhen Chen,¹ Miguel Omar Velardez,¹ Xavier Warot,¹ Zhao-Xue Yu,¹ Shyra J. Miller,³ Didier Cros,² and Gabriel Corfas¹

¹Division of Neuroscience, Children’s Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, ²Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02129, and ³Department of Pediatrics, University of Cincinnati, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio 45229-7013

Correspondence should be addressed to Dr. Gabriel Corfas, Division of Neuroscience, Children’s Hospital, 300 Longwood Avenue, Boston, MA 02115. Email: gabriel.corfas{at}childrens.harvard.edu

To investigate the role of erbB signaling in the interactions between peripheral axons and myelinating Schwann cells, we generated transgenic mice expressing a dominant-negative erbB receptor in these glial cells. Mutant mice have delayed onset of myelination, thinner myelin, shorter internodal length, and smaller axonal caliber in adulthood. Consistent with the morphological defects, transgenic mice also have slower nerve conduction velocity and defects in their responses to mechanical stimulation. Molecular analysis indicates that erbB signaling may contribute to myelin formation by regulating transcription of myelin genes. Analysis of sciatic nerves showed a reduction in the levels of expression of myelin genes in mutant mice. In vitro assays revealed that neuregulin-1 (NRG1) induces expression of myelin protein zero (P0). Furthermore, we found that the effects of NRG1 on P0 expression depend on the NRG1 isoform used. When NRG1 is presented to Schwann cells in the context of cell–cell contact, type III but not type I NRG1 regulates P0 gene expression. These results suggest that disruption of the NRG1–erbB signaling pathway could contribute to the pathogenesis of peripheral neuropathies with hypomyelination and neuropathic pain.

Key words: Schwann cell; myelin protein zero; pain; sciatic nerve; transgenic mouse; neuregulin

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Received Sept. 7, 2005; revised Jan. 4, 2006; accepted Feb. 6, 2006.

Correspondence should be addressed to Dr. Gabriel Corfas, Division of Neuroscience, Children’s Hospital, 300 Longwood Avenue, Boston, MA 02115. Email: gabriel.corfas{at}childrens.harvard.edu

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