Gpr126 Contributes To The Terminal Schwann Cell Injury Response At The Neuromuscular Junction
Albina Jablonka-Shariff, PhD1, Johnny Chuieng-Yi Lu, MD, MS1, Katherine Campbell, BA1, Kelly R. Monk, PhD2, Alison K. Snyder-Warwick, MD1.
1Washington University School of Medicine, St. Louis, MO, USA, 2Vollum Institute, Oregon Health and Science University, Portland, OR, USA.
PURPOSE: Gpr126 is an adhesion G protein-coupled receptor essential for Schwann cell (SC) myelination with important contributions to repair after nerve crush injury. Despite critical functions in myelinating SCs, the role of Gpr126 within non-myelinating terminal Schwann cells (tSCs) at the neuromuscular junction (NMJ), is not known. tSCs have important functions in synaptic maintenance and reinnervation, and after injury tSCs extend cytoplasmic processes to guide regenerating axons to the denervated NMJ. In this study, we evaluate the contributions of Gpr126 to tSCs after nerve injury.
METHODS: A SC-specific conditional Gpr126 knockout model, DhhCre;Gpr126fl/fl mice, hereafter called cGpr126 mice, underwent spinal accessory nerve transection and primary repair. NMJ structures, NMJ reinnervation, and immune mediators were assessed in the sternomastoid (SM) muscles from both the injured and sham uninjured sides at 1, 3, or 6 weeks following nerve transection and repair with immunostaining and qRT-PCR.
RESULTS: Gpr126 is expressed in tSCs. cGpr126 mice display delayed NMJ reinnervation, altered tSC morphology with decreased S100β expression and reduced tSC cytoplasmic process extensions. The immune response promoting reinnervation at the NMJ following nerve injury is also altered with decreased macrophage infiltration, Tnfα, and anomalous cytokine expression compared to NMJs of control mice. In addition, Vegfa expression is decreased in muscle, suggesting that cGpr126 non-cell autonomously modulates angiogenesis after nerve injury.
CONCLUSION: Gpr126 is required for tSC process elongation for successful NMJ reinnervation in the muscle. We also show that Gpr126 deficiency in SCs delays the immune response in muscle, necessary for reinnervation, after nerve injury. Gpr126 signaling, therefore, is integral not only to myelinating SCs, but also to non-myelinating tSC function at the NMJ. The integral function of Gpr126 in tSCs at the NMJ provides the framework for new therapeutic targets for neuromuscular disease.
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