Schwann cells (SCs) detect injury to peripheral nerves and transform phenotypically to respond to injury and facilitate repair. Cell-signaling pathways and changes in gene expression that drive SC phenotypic transformation in injury have been described; however, the SC receptors that detect peripheral nervous system (PNS) injury have not been identified. LDL receptor-related protein 1 (LRP1) is a receptor for numerous ligands, including intracellular proteins released by injured cells and protein components of degenerated myelin. In certain cell types, including SCs, LRP1 is a cell-signaling receptor. Here, we show that binding of the LRP1 ligand, tissue-type plasminogen activator (tPA), to cultured rat SCs induces c-Jun phosphorylation, a central event in activation of the SC repair program. The response to tPA was blocked by the LRP1 antagonist, receptor-associated protein. c-Jun phosphorylation was also observed when cultured rat SCs were treated with a recombinant derivative of matrix metalloproteinase-9 that contains the LRP1 recognition motif (PEX). The ability of LRP1 to induce c-Jun phosphorylation and ERK1/2 activation was confirmed using cultures of human SCs. When tPA or PEX was injected directly into crush-injured rat sciatic nerves, c-Jun phosphorylation and ERK1/2 activation were observed in SCs in vivo. The ability of LRP1 to bind proteins released in the earliest stages of PNS injury and to induce c-Jun phosphorylation support a model in which SC LRP1 functions as an injury-detection receptor in the PNS.

Schwann cells (SCs) detect injury to peripheral nerves and transform phenotypically to respond to injury and facilitate repair. Cell-signaling pathways and changes in gene expression that drive SC phenotypic transformation in injury have been described; however, the SC receptors that detect peripheral nervous system (PNS) injury have not been identified. LDL receptor-related protein 1 (LRP1) is a receptor for numerous ligands, including intracellular proteins released by injured cells and protein components of degenerated myelin. In certain cell types, including SCs, LRP1 is a cell-signaling receptor. Here, we show that binding of the LRP1 ligand, tissue-type plasminogen activator (tPA), to cultured rat SCs induces c-Jun phosphorylation, a central event in activation of the SC repair program. The response to tPA was blocked by the LRP1 antagonist, receptor-associated protein. c-Jun phosphorylation was also observed when cultured rat SCs were treated with a recombinant derivative of matrix metalloproteinase-9 that contains the LRP1 recognition motif (PEX). The ability of LRP1 to induce c-Jun phosphorylation and ERK1/2 activation was confirmed using cultures of human SCs. When tPA or PEX was injected directly into crush-injured rat sciatic nerves, c-Jun phosphorylation and ERK1/2 activation were observed in SCs in vivo. The ability of LRP1 to bind proteins released in the earliest stages of PNS injury and to induce c-Jun phosphorylation support a model in which SC LRP1 functions as an injury-detection receptor in the PNS.

Schwann cells (SCs) undergo phenotypic transformation and then orchestrate nerve repair following PNS injury. The ligands and receptors that activate and sustain SC transformation remain incompletely understood. Proteins released by injured axons represent important candidates for activating the SC Repair Program. The low-density lipoprotein receptor-related protein-1 (LRP1) is acutely up-regulated in SCs in response to injury, activating c-Jun, and promoting SC survival. To identify novel LRP1 ligands released in PNS injury, we applied a discovery-based approach in which extracellular proteins in the injured nerve were captured using Fc-fusion proteins containing the ligand-binding motifs of LRP1 (CCR2 and CCR4). An intracellular neuron-specific protein, Protein Kinase C and Casein Kinase Substrate in Neurons (PACSIN1) was identified and validated as an LRP1 ligand. Recombinant PACSIN1 activated c-Jun and ERK1/2 in cultured SCs. Silencing Lrp1 or inhibiting the LRP1 cell-signaling co-receptor, the NMDA-R, blocked the effects of PACSIN1 on c-Jun and ERK1/2 phosphorylation. Intraneural injection of PACSIN1 into crush-injured sciatic nerves activated c-Jun in wild-type mice, but not in mice in which Lrp1 is conditionally deleted in SCs. Transcriptome profiling of SCs revealed that PACSIN1 mediates gene expression events consistent with transformation to the repair phenotype. PACSIN1 promoted SC migration and viability following the TNFα challenge. When Src family kinases were pharmacologically inhibited or the receptor tyrosine kinase, TrkC, was genetically silenced or pharmacologically inhibited, PACSIN1 failed to induce cell signaling and prevent SC death. Collectively, these studies demonstrate that PACSIN1 is a novel axon-derived LRP1 ligand that activates SC repair signaling by transactivating TrkC.