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Merlin isoform 2 in neurofibromatosis type 2–associated polyneuropathy

Nature Neuroscience volume 16, pages 426–433 (2013)Cite this article

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Abstract

The autosomal dominant disorder neurofibromatosis type 2 (NF2) is a hereditary tumor syndrome caused by inactivation of the NF2 tumor suppressor gene, encoding merlin. Apart from tumors affecting the peripheral and central nervous systems, most NF2 patients develop peripheral neuropathies. This peripheral nerve disease can occur in the absence of nerve-damaging tumors, suggesting an etiology that is independent of gross tumor burden. We discovered that merlin isoform 2 (merlin-iso2) has a specific function in maintaining axonal integrity and propose that reduced axonal NF2 gene dosage leads to NF2-associated polyneuropathy. We identified a merlin-iso2–dependent complex that promotes activation of the GTPase RhoA, enabling downstream Rho-associated kinase to promote neurofilament heavy chain phosphorylation. Merlin-iso2–deficient mice exhibited impaired locomotor capacities, delayed sensory reactions and electrophysiological signs of axonal neuropathy. Sciatic nerves from these mice and sural nerve biopsies from NF2 patients revealed reduced phosphorylation of the neurofilament H subunit, decreased interfilament spacings and irregularly shaped axons.

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Figure 1: Merlin-iso2 expressed in axons, mediates neurofilament phosphorylation and axonal radial growth.
Figure 2: Merlin mediates neurofilament phosphorylation via the Rho-ROCK pathway.
Figure 3: Merlin assembles a multi-protein complex relevant for Rho activation.
Figure 4: Axon structure abnormalities in Nf2-iso2−/− mice.
Figure 5: Reduced interfilament distances in Nf2-iso2−/− mice.
Figure 6: Behavioral abnormalities in Nf2-iso2−/− mice.
Figure 7: NF2 patient biopsies display neurofilament hypophosphorylation.

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Acknowledgements

The authors would like to thank U. Petz, C. Poser and S. Ramrath for their expert technical assistance, H. Rosemann, F. Kaufmann and D. Galendo for their skilled breeding and husbandry of animals, and R.E. Ferner for discussions and support. Mpz-cre mice were kindly provided M.L. Feltri (Hunter James Kelly Research Institute). This work was supported by Sonderforschungsbereich 604, Deutsche Forschungsgemeinschaft MO 1421/2–1 and Krebshilfe 107089. A.S. is recipient of a Young Investigator Award from the Children's Tumor Foundation.

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Author notes

  1. Michiko Niwa-Kawakita

    Present address: Present address: Inserm U944, CNRS U7212, Université Paris, Institut Universitaire d'Hématologie, Paris, France.,

  2. Stephan L Baader and Michiko Niwa-Kawakita: These authors contributed equally to this work.

Authors and Affiliations

  1. Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany

    Alexander Schulz, Marie Juliane Jung, Ansgar Zoch, Stephan Schacke & Helen Morrison

  2. Institute of Anatomy, Anatomy and Cell Biology, University of Bonn, Bonn, Germany

    Stephan L Baader

  3. Inserm U674, Université Paris, Paris, France

    Michiko Niwa-Kawakita

  4. Institute of Molecular Cell Biology and Center for Sepsis Control and Care, Jena University Hospital, Friedrich Schiller University, Jena, Germany

    Reinhard Bauer

  5. Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA

    Cynthia Garcia & David H Gutmann

  6. Department of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Christian Hagel

  7. Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Victor-Felix Mautner

  8. Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK

    C Oliver Hanemann, Xin-Peng Dun & David B Parkinson

  9. Institute of Neuropathology, RWTH Aachen, University Hospital Aachen, Aachen, Germany

    Joachim Weis & J Michael Schröder

  10. House Ear Institute, Center for Neural Tumor Research, Los Angeles, California, USA

    Marco Giovannini

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Contributions

A.S. and H.M. conceived and designed the study. H.M. supervised the experimental program and prepared the manuscript. A.S. performed and analyzed the majority of the experiments and prepared the manuscript. S.L.B. performed the nerve section analysis of both knockout mice and patient biopsies, as well as their analysis. M.N.-K. and M.G. generated the Nf2-iso1−/− and Nf2-iso2−/− mice. R.B. designed the electrophysiological experiments and participated in data acquisition. C.G. and D.H.G. synthesized isoform-specific merlin antibodies. A.Z. and M.J.J. participated in the behavioral analysis of merlin knockout mice and the preparation of primary cell cultures. S.S. conducted nucleotide exchange and binding assays. X.-P.D. and D.B.P. provided tissue samples of Mpz-cre; Nf2loxP/loxP mice. C.H. and V.-F.M. provided NF2 patient biopsy sections for immunohistochemistry. C.O.H. provided NF2 patient biopsy sections for ultrastructural analysis. J.W. and J.M.S. performed the ultrastructural analysis of human NF2 patient biopsies.

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Correspondence to Helen Morrison.

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Schulz, A., Baader, S., Niwa-Kawakita, M. et al. Merlin isoform 2 in neurofibromatosis type 2–associated polyneuropathy. Nat Neurosci 16, 426–433 (2013). https://doi.org/10.1038/nn.3348

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