Abstract

Glial cells regulate multiple aspects of synaptogenesis. In the absence of Schwann cells, a peripheral glial cell, motor neurons initially innervate muscle but then degenerate. Here, using a genetic approach, we show that neural activity-regulated negative factors produced by muscle drive neurodegeneration in Schwann cell-deficient mice. We find that thrombin, the hepatic serine protease central to the hemostatic coagulation cascade, is one such negative factor. Trancriptomic analysis shows that expression of the antithrombins serpin C1 and D1 is significantly reduced in Schwann cell-deficient mice. In the absence of peripheral neuromuscular activity, neurodegeneration is completely blocked, and expression of prothrombin in muscle is markedly reduced. In the absence of muscle-derived prothrombin, neurodegeneration is also markedly reduced. Together, these results suggest that Schwann cells regulate NMJs by opposing the effects of activity-regulated, muscle-derived negative factors and provide the first genetic evidence that thrombin plays a central role outside of the coagulation system.

Highlights

  • Synapses are the key elements of neural circuits underlying nervous system function

  • We searched for the molecular basis of this effect by examining the transcriptomes in the muscle of control mice with Schwann cells and erbB3 mutant mice without them

  • We found evidence that a negative signal expressed by muscle was regulated by neural activity and normally blocked by factors produced in Schwann cells

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Summary

Introduction

Synapses are the key elements of neural circuits underlying nervous system function. understanding cellular and molecular mechanisms of synapse formation and maintenance is fundamental to neurobiology. Establishment of the mature pattern of neuronal connectivity is achieved by the formation, differentiation, refinement and maintenance of specialized synaptic contacts between pre-, peri- and post-synaptic cells. The muscle-specific kinase (MuSK), low-density lipoprotein receptorrelated protein 4 (Lrp4) and adaptor protein rapsyn are required for the formation of the spatially restricted pattern of the postsynaptic apparatus, including acetylcholine receptor (AChR) clusters, known as the endplate band, whereas motor nerve-derived signals such as agrin and acetylcholine (ACh) play opposing roles in the refinement and maintenance of the postsynaptic apparatus [3,4,5,6,7,8,9,10,11,12,13]. Muscle-derived factors such as β-catenin, Lrp, fibroblast growth factors and laminin β2 are required for branch positioning, presynaptic differentiation and maturation of motor neurons [14,15,16,17,18,19]

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