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.

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    Human-specific cognitive abilities depend on information processing in the cerebral cortex, where the neurons are significantly larger and their processes longer and sparser compared to rodents. We found that, in synaptically connected layer 2/3 pyramidal cells (L2/3 PCs), the delay in signal propagation from soma to soma is similar in humans and rodents. To compensate for the longer processes of neurons, membrane potential changes in human axons and/or dendrites must propagate faster. Axonal and dendritic recordings show that the propagation speed of action potentials (APs) is similar in human and rat axons, but the forward propagation of excitatory postsynaptic potentials (EPSPs) and the backward propagation of APs are 26 and 47% faster in human dendrites, respectively. Experimentally-based detailed biophysical models have shown that the key factor responsible for the accelerated EPSP propagation in human cortical dendrites is the large conductance load imposed at the soma by the large basal dendritic tree. Additionally, larger dendritic diameters and differences in cable and ion channel properties in humans contribute to enhanced signal propagation. Our integrative experimental and modeling study provides new insights into the scaling rules that help maintain information processing speed albeit the large and sparse neurons in the human cortex.