Abstract

Myelination is essential for nervous system function. Schwann cells interact with neurons and the basal lamina to myelinate axons using known receptors, signals and transcription factors. In contrast, the transcriptional control of axonal sorting and the role of mechanotransduction in myelination are largely unknown. Yap and Taz are effectors of the Hippo pathway that integrate chemical and mechanical signals in cells. We describe a previously unknown role for the Hippo pathway in myelination. Using conditional mutagenesis in mice, we show that Taz is required in Schwann cells for radial sorting and myelination and that Yap is redundant with Taz. Yap and Taz are activated in Schwann cells by mechanical stimuli and regulate Schwann cell proliferation and transcription of basal lamina receptor genes, both necessary for radial sorting of axons and subsequent myelination. These data link transcriptional effectors of the Hippo pathway and of mechanotransduction to myelin formation in Schwann cells.

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Acknowledgements

We thank E. Hurley for technical assistance; A. Sonnenberg (Netherlands Cancer Institute), D. Meijer and P. Brophy (Centre for Neuroregeneration, Edinburgh), the late G. Tarone (University of Turin), L. Sorokin (University of Muenster) and M. Wegner (Friedrich-Alexander University Erlangen–Nürnberg) for antibodies, and the late R. Quarles (National Institute of Neurological Diseases and Stroke) for the S16 cells. This work was funded by grants NS045630 (to M.L.F.), NS096104 (to L.W.) and NS075269 (to J.S.).

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Affiliations

  1. Department of Biochemistry, Hunter James Kelly Research Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York, USA.

    • Yannick Poitelon
    • , Kathleen Catignas
    • , Caterina Berti
    • , Marilena Palmisano
    • , Courtney Williamson
    • , Dominique Ameroso
    • , Kansho Abiko
    • , Yoonchan Hwang
    • , Lawrence Wrabetz
    •  & Maria Laura Feltri
  2. Waisman Center, University of Wisconsin–Madison, Madison, Wisconsin, USA.

    • Camila Lopez-Anido
    •  & John Svaren
  3. Lunenfeld–Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.

    • Alex Gregorieff
    •  & Jeffrey L Wrana
  4. Department of Biomedical Engineering, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York, USA.

    • Mohammadnabi Asmani
    •  & Ruogang Zhao
  5. Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York, USA.

    • Fraser James Sim
  6. Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York, USA.

    • Lawrence Wrabetz
    •  & Maria Laura Feltri

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Contributions

Y.P., K.C., C.B., M.P. and M.L.F. designed research and interpreted data; Y.P. performed experiments with assistance from C.L.-A., K.C., C.B., M.P., C.W., D.A., K.A. and Y.H.; C.L.-A. and J.S. designed and performed ChIP sequencing and promoter analysis. M.A. and R.Z. designed and helped to perform biomechanical experiments; A.G. and J.L.W. and L.W. contributed analytical tools; F.J.S. analyzed RNA-seq data; Y.P. and M.L.F. wrote the manuscript; Y.P., C.L.-A., R.Z., F.J.S., J.S., L.W. and M.L.F. analyzed data and critically reviewed the manuscript.

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The authors declare no competing financial interests.

Corresponding author

Correspondence to Maria Laura Feltri.

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    Supplementary Table 1

    Genes differentially expressed in Taz cKO–Yap cHet with a false discovery rate of 5% or lower.

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https://doi.org/10.1038/nn.4316

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