Activation of the Wnt/β-catenin signaling cascade after traumatic nerve injury

S. Kurimoto, J. Jung, M. Tapadia, J. Lengfeld, D. Agalliu, M. Waterman, T. Mozaffar, R. Gupta

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Recent data have shown that preservation of the neuromuscular junction (NMJ) after traumatic nerve injury helps to improve functional recovery with surgical repair via matrix metalloproteinase-3 (MMP3) blockade. As such, we sought to explore additional pathways that may augment this response. Wnt3a has been shown to inhibit acetylcholine receptor (AChR) clustering via β-catenin-dependent signaling in the development of the NMJ. Therefore, we hypothesized that Wnt3a and β-catenin are associated with NMJ destabilization following traumatic denervation. A critical size nerve defect was created by excising a 10-mm segment of the sciatic nerve in mice. Denervated muscles were then harvested at multiple time points for immunofluorescence staining, quantitative real-time PCR, and western blot analysis for Wnt3a and β-catenin levels. Moreover, a novel Wnt/β-catenin transgenic reporter mouse line was utilized to support our hypothesis of Wnt activation after traumatic nerve injury. The expression of Wnt3a mRNA was significantly increased by 2. weeks post-injury and remained upregulated for 2. months. Additionally, β-catenin was activated at 2. months post-injury relative to controls. Correspondingly, immunohistochemical analysis of denervated transgenic mouse line TCF/Lef:H2B-GFP muscles demonstrated that the number of GFP-positive cells was increased at the motor endplate band. These collective data support that post-synaptic AChRs destabilize after denervation by a process that involves the Wnt/β-catenin pathway. As such, this pathway serves as a potential therapeutic target to prevent the motor endplate degeneration that occurs following traumatic nerve injury.

Original languageEnglish (US)
Pages (from-to)101-108
Number of pages8
JournalNeuroscience
Volume294
DOIs
StatePublished - May 1 2015
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2015 IBRO.

Keywords

  • Neuromuscular junction
  • Peripheral nerve
  • Traumatic nerve injury
  • Wnt signaling

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