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Gpr126 Contributes to Terminal Schwann Cell Function after Nerve Injury
Alison K. Snyder-Warwick, MD; Katherine Santosa, MD; Albina Jablonka Shariff, PhD
Washington University, Saint Louis, MO
Introduction: Terminal Schwann cells (tSCs), non-myelinating glia cells at the neuromuscular junction (NMJ), contribute to NMJ reinnervation after injury, and represent an excellent potential cell type to target to improve functional recovery. After nerve injury and NMJ denervation, tSCs extend cytoplasmic processes away from the NMJ in search of nearby axons. Gpr126, an adhesion G-protein coupled receptor, is essential for the development and function of myelinating Schwann cells (SCs). The function of Gpr126 in tSC biology, however, is unknown. We hypothesize that Gpr126 is essential for tSC contributions to NMJ reinnervation after peripheral nerve injury.
Method: The spinal accessory nerve (SAN) was unilaterally transected and immediately repaired in DhhCre;Gpr126fl/fl conditional knockout (cGpr126-KO) mice, in which Gpr126 is deleted in mature SCs, and was compared to sibling controls for the study. The NMJs in the sternomastoid (SM) muscle were evaluated at 1, 2, and 3 weeks following nerve injury via immunofluorescence and confocal microscopy.
Results: Three weeks after injury, control mice showed extensive NMJ regeneration. In contrast, NMJ reinnervation was compromised in SM from cGpr126-KO mice compared to the uninjured contralateral side or to sibling controls. In the cGpr126-KO mice, acetylcholine receptors (AChRs) were partially fragmented. Nerve terminals partially colocalized with AChRs or were absent in some NMJs, but showed collateral sprouting in others. Lower tSC numbers were noted in the cGpr126-KO mice without injury, but thicker and more numerous tSC processes were noted after nerve injury in the cGpr126-KO mice compared to controls. In addition, significantly higher numbers of macrophages were observed at the NMJs.
Conclusion: cGpr126-KO mice showed delayed NMJ reinnervation 3 weeks following peripheral nerve injury. These data support a model in which Gpr126 is required for tSC contributions to NMJ reinnervation after peripheral nerve injury. The information gained from this research has important implications regarding development, injury, and repair of the NMJ, which may lead to translational research to improve recovery following peripheral nerve injury.
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