Gpr126/Adgrg6 contributes to the terminal Schwann cell response at the neuromuscular junction following peripheral nerve injury

Abstract

Gpr126/Adgrg6 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 nonmyelinating 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 show that Gpr126 is expressed in tSCs, and that absence of Gpr126 in SCs (SC‐specific Gpr126 knockout, cGpr126) results in a NMJ maintenance defect in the hindlimbs of aged mice, but not in young adult mice. After nerve transection and repair, 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. In sum, cGpr126 mice demonstrated delayed NMJ reinnervation and decreased muscle mass following nerve transection and repair compared to control littermates. The integral function of Gpr126 in tSCs at the NMJ provides the framework for new therapeutic targets for neuromuscular disease.

Dimeric prion protein ligand activates Adgrg6 but does not rescue myelinopathy of PrP-deficient mice

“…In addition, Adgrg6 is involved in the remyelination of axons (Mogha et al, 2016) and reinnervation of neuromuscular junctions (Jablonka-Shariff et al, 2020) after nerve injury. Whereas the inducible knockout of Adgrg6 in Schwann cells did not result in signs of demyelination for up to 4 months (Mogha et al, 2016), aged conditional Adgrg6 knockout mice showed neuromuscular junction alterations and signs of denervation in hindlimbs, consistent with chronic disruption of Schwann cell function (Jablonka-Shariff et al, 2020). Together with the 5 late-onset demyelinating neuropathy of PrP knockout mice, these findings suggest that Adgrg6 is not only required for the initiation of myelination, but also for long-term myelin maintenance.…”

The prion protein is not required for peripheral nerve repair after crush injury

“…Adgrg6 is expressed in Schwann cells and was shown to have autonomous and nonautonomous functions in peripheral nerve repair (4,5). PrP is an agonist of Adgrg6 on Schwann cells (8).…”

“…The reciprocal interaction between axons, Schwann cells and the extracellular matrix is crucial for development, maintenance and repair of the peripheral nervous system (PNS) (1,2). The adhesion G-protein coupled receptor Adgrg6 (formerly called Gpr126) was shown to be required for Schwann cell development (3), peripheral nerve repair (4,5) and possibly myelin maintenance (4). Three natural ligands for Adgrg6 have been described: collagen IV (6), laminin-211 (7) and the prion protein (PrP) (8).…”

The prion protein is not required for peripheral nerve de- and remyelination after crush injury

“…Later, a contribution of Adgrg6 to macrophage recruitment and remyelination after nerve crush injury was demonstrated [ 12 ], indicating that Adgrg6 is also involved in PNS repair. Furthermore, Adgrg6 is required for responses of terminal Schwann cells and regeneration of neuromuscular junctions [ 13 ], which is crucial for the restoration of function after peripheral nerve injury. Finally, ageing conditional Adgrg6 knockout mice showed signs of hindlimb denervation [ 13 ], suggesting a role of Adgrg6 signaling in maintenance of peripheral myelin.…”

“…Furthermore, Adgrg6 is required for responses of terminal Schwann cells and regeneration of neuromuscular junctions [ 13 ], which is crucial for the restoration of function after peripheral nerve injury. Finally, ageing conditional Adgrg6 knockout mice showed signs of hindlimb denervation [ 13 ], suggesting a role of Adgrg6 signaling in maintenance of peripheral myelin. This notion is supported by the development of a progressive demyelinating neuropathy of the PNS in mice devoid of the cellular prion protein (PrP), an agonist of Adgrg6 [ 14 , 15 ].…”