Abstract

Nuclear exclusion of the transcriptional regulators and potent oncoproteins, YAP/TAZ, is considered necessary for adult tissue homeostasis. Here we show that nuclear YAP/TAZ are essential regulators of peripheral nerve development and maintenance. To proliferate, developing Schwann cells (SCs) require YAP/TAZ to enter S-phase and, without them, fail to generate sufficient SCs for timely axon sorting. To differentiate, SCs require YAP/TAZ to upregulate Krox20 and, without them, completely fail to myelinate, resulting in severe peripheral neuropathy. Remarkably, in adulthood, nuclear YAP/TAZ are selectively expressed by myelinating SCs, and conditional ablation results in severe peripheral demyelination and mouse death. YAP/TAZ regulate both developmental and adult myelination by driving TEAD1 to activate Krox20. Therefore, YAP/TAZ are crucial for SCs to myelinate developing nerve and to maintain myelinated nerve in adulthood. Our study also provides a new insight into the role of nuclear YAP/TAZ in homeostatic maintenance of an adult tissue.

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Author details

  1. Matthew Grove

    Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Hyukmin Kim

    Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Maryline Santerre

    FELS Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Alexander J Krupka

    Department of Bioengineering, Temple University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Seung Baek Han

    Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Jinbin Zhai

    Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Jennifer Y Cho

    Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Raehee Park

    Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Michele Harris

    Department of Anatomy and Cell Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Seonhee Kim

    Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Bassel E Sawaya

    FELS Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Shin H Kang

    Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Mary F Barbe

    Department of Anatomy and Cell Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Seo-Hee Cho

    Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Michel A Lemay

    Department of Bioengineering, Temple University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Young-Jin Son

    Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, United States
    For correspondence
    yson@temple.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5725-9775

Funding

National Institute of Neurological Disorders and Stroke (NS079631)

  • Young-Jin Son

Shriners Hospitals for Children (research grant,86600)

  • Young-Jin Son

National Institute of Neurological Disorders and Stroke (NS076401)

  • Bassel E Sawaya

National Institute of Mental Health (MH093331)

  • Bassel E Sawaya

National Institute of Neurological Disorders and Stroke (NS095070)

  • Young-Jin Son

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#4254, #4255) of the Temple University.

Copyright

© 2017, Grove et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Matthew Grove
  2. Hyukmin Kim
  3. Maryline Santerre
  4. Alexander J Krupka
  5. Seung Baek Han
  6. Jinbin Zhai
  7. Jennifer Y Cho
  8. Raehee Park
  9. Michele Harris
  10. Seonhee Kim
  11. Bassel E Sawaya
  12. Shin H Kang
  13. Mary F Barbe
  14. Seo-Hee Cho
  15. Michel A Lemay
  16. Young-Jin Son
(2017)
YAP/TAZ initiate and maintain Schwann cell myelination
eLife 6:e20982.
https://doi.org/10.7554/eLife.20982

Share this article

https://doi.org/10.7554/eLife.20982

Further reading

    1. Neuroscience
    Matthew Grove, Hyunkyoung Lee ... Young-Jin Son
    Research Advance Updated

    Previously we showed that YAP/TAZ promote not only proliferation but also differentiation of immature Schwann cells (SCs), thereby forming and maintaining the myelin sheath around peripheral axons (Grove et al., 2017). Here we show that YAP/TAZ are required for mature SCs to restore peripheral myelination, but not to proliferate, after nerve injury. We find that YAP/TAZ dramatically disappear from SCs of adult mice concurrent with axon degeneration after nerve injury. They reappear in SCs only if axons regenerate. YAP/TAZ ablation does not impair SC proliferation or transdifferentiation into growth promoting repair SCs. SCs lacking YAP/TAZ, however, fail to upregulate myelin-associated genes and completely fail to remyelinate regenerated axons. We also show that both YAP and TAZ are redundantly required for optimal remyelination. These findings suggest that axons regulate transcriptional activity of YAP/TAZ in adult SCs and that YAP/TAZ are essential for functional regeneration of peripheral nerve.

    1. Neuroscience
    Simonas Griesius, Amy Richardson, Dimitri Michael Kullmann
    Research Article

    Non-linear summation of synaptic inputs to the dendrites of pyramidal neurons has been proposed to increase the computation capacity of neurons through coincidence detection, signal amplification, and additional logic operations such as XOR. Supralinear dendritic integration has been documented extensively in principal neurons, mediated by several voltage-dependent conductances. It has also been reported in parvalbumin-positive hippocampal basket cells, in dendrites innervated by feedback excitatory synapses. Whether other interneurons, which support feed-forward or feedback inhibition of principal neuron dendrites, also exhibit local non-linear integration of synaptic excitation is not known. Here, we use patch-clamp electrophysiology, and two-photon calcium imaging and glutamate uncaging, to show that supralinear dendritic integration of near-synchronous spatially clustered glutamate-receptor mediated depolarization occurs in NDNF-positive neurogliaform cells and oriens-lacunosum moleculare interneurons in the mouse hippocampus. Supralinear summation was detected via recordings of somatic depolarizations elicited by uncaging of glutamate on dendritic fragments, and, in neurogliaform cells, by concurrent imaging of dendritic calcium transients. Supralinearity was abolished by blocking NMDA receptors (NMDARs) but resisted blockade of voltage-gated sodium channels. Blocking L-type calcium channels abolished supralinear calcium signalling but only had a minor effect on voltage supralinearity. Dendritic boosting of spatially clustered synaptic signals argues for previously unappreciated computational complexity in dendrite-projecting inhibitory cells of the hippocampus.