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Myelin Basic Protein Cleaves Cell Adhesion Molecule L1 and Improves Regeneration After Injury

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Abstract

Myelin basic protein (MBP) is a serine protease that cleaves neural cell adhesion molecule L1 and generates a transmembrane L1 fragment which facilitates L1-dependent functions in vitro, such as neurite outgrowth, neuronal cell migration and survival, myelination by Schwann cells as well as Schwann cell proliferation, migration, and process formation. Ablation and blocking of MBP or disruption of its proteolytic activity by mutation of a proteolytically active serine residue abolish L1-dependent cellular responses. In utero injection of adeno-associated virus encoding proteolytically active MBP into MBP-deficient shiverer mice normalizes differentiation, myelination, and synaptogenesis in the developing postnatal spinal cord, in contrast to proteolytically inactive MBP. Application of active MBP to the injured wild-type spinal cord and femoral nerve augments levels of a transmembrane L1 fragment, promotes remyelination, and improves functional recovery after injury. Application of MBP antibody impairs recovery. Virus-mediated expression of active MBP in the lesion site after spinal cord injury results in improved functional recovery, whereas injection of virus encoding proteolytically inactive MBP fails to do so. The present study provides evidence for a novel L1-mediated function of MBP in the developing spinal cord and in the injured adult mammalian nervous system that leads to enhanced recovery after acute trauma.

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Acknowledgments

We are very grateful to David Colman for the gift of antibody against the exon II-encoded domain of mouse MBP. We appreciate the excellent technical assistance from Ute Bork, Emanuela Szpotowicz, Dagmar Drexler, Barbara Holstermann, Fritz Kutschera and Torsten Renz, Eva Kronberg and Ulrike Wolters for breeding and maintenance of mice, and Gabriele Rune for the possibility to use the electron microscope. Bin Wu was supported by the National Natural Science Foundation of China (81000520). Melitta Schachner is supported by the New Jersey Commission for Spinal Cord Research and the Li Ka-Shing Foundation at Shantou University Medical College.

Conflict of Interest

The authors declare that they have no competing interests.

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Author notes

  1. Daria Guseva

    Present address: Department of Cellular Neurobiology, Medical School Hannover, Hannover, Germany

Authors and Affiliations

  1. Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany

    David Lutz, Hardeep Kataria, Ralf Kleene, Gabriele Loers, Harshita Chaudhary, Daria Guseva, Bin Wu & Igor Jakovcevski

  2. Melitta Schachner, Center for Neuroscience, Shantou University Medical College, 22 Xin Ling Road, Shantou, Guangdong, 515041, China

    Melitta Schachner

  3. Keck Center for Collaborative Neuroscience and Department of Cell Biology and Neuroscience, Rutgers University, 604 Allison Road, Piscataway, NJ, 08854, USA

    Melitta Schachner

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  1. David Lutz
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Lutz, D., Kataria, H., Kleene, R. et al. Myelin Basic Protein Cleaves Cell Adhesion Molecule L1 and Improves Regeneration After Injury. Mol Neurobiol 53, 3360–3376 (2016). https://doi.org/10.1007/s12035-015-9277-0

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