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The Journal of Neuroscience, June 21, 2006, 26(25):6873-6884; doi:10.1523/JNEUROSCI.1086-06.2006

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Development/Plasticity/Repair
Induction of Neuregulin Signaling in Mouse Schwann Cells In Vivo Mimics Responses to Denervation

Christopher R. Hayworth,¹ Susan E. Moody,³ Lewis A. Chodosh,³ Paul Krieg,⁴ Mendell Rimer,^1,2 and Wesley J. Thompson^1,2

¹Section of Neurobiology and Institute for Neuroscience and ²Institute for Cellular and Molecular Biology, University of Texas, Austin, Texas 78712, ³Abramson Family Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, and ⁴Department of Cell Biology and Anatomy, University of Arizona College of Medicine, Tucson, Arizona 85724

Correspondence should be addressed to either Mendell Rimer or Wesley J. Thompson, Section of Neurobiology C0920, University of Texas, Austin, TX 78712. Email: rimer{at}mail.utexas.edu or wes{at}mail.utexas.edu

Neuregulins play crucial roles in early development of Schwann cells (SCs), but their roles in the activities of SCs during denervation and reinnervation of muscle are less clear. In the present study, the Tet-On system has been used in transgenic mice to enable inducible expression of a mutant, constitutively active neuregulin receptor (ErbB2) in SCs. This induction simulates neuregulin signaling to these cells. Reporter transgenes were used to show a tightly regulated, SC-selective expression in muscle. Induction leads to a number of changes in SCs at neuromuscular junctions that mimic the response to muscle denervation/reinnervation. These include process extension, soma migration, and proliferation. SCs also come to express nestin, a protein characteristic of their reaction to muscle denervation. This activation of SCs results in the sprouting of nerve terminals, and these sprouts follow the extensions of the SCs. However, these sprouts and their associated SCs disappear after the removal of the inducer. Last, induction of the active receptor is sufficient to rescue SCs in neonatal muscle from denervation-induced apoptosis. These findings show that the responses of SCs in muscle to denervation can be explained by induction of an autocrine/paracrine neuregulin signaling cascade suggested by previous molecular studies.

Key words: neuromuscular junction; terminal Schwann cell; S100B; GGF; ErbB receptor; Neu; Tet-On; rtTA; nestin; cell migration; sprouting; cell proliferation

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Received March 14, 2006; revised April 22, 2006; accepted May 19, 2006.

Correspondence should be addressed to either Mendell Rimer or Wesley J. Thompson, Section of Neurobiology C0920, University of Texas, Austin, TX 78712. Email: rimer{at}mail.utexas.edu or wes{at}mail.utexas.edu

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