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PI3K-Yap activity drives cortical gyrification and hydrocephalus in mice

  1. Achira Roy
  2. Rory M Murphy
  3. Mei Deng
  4. James W MacDonald
  5. Theo K Bammler
  6. Kimberly A Aldinger
  7. Ian A Glass
  8. Kathleen J Millen  Is a corresponding author
  1. Seattle Children's Research Institute, United States
  2. University of Washington, United States
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Cite this article as: eLife 2019;8:e45961 doi: 10.7554/eLife.45961

Abstract

Mechanisms driving the initiation of brain folding are incompletely understood. We have previously characterized mouse models recapitulating human PIK3CA-related brain overgrowth, epilepsy, dysplastic gyrification and hydrocephalus (Roy et al., 2015). Using the same, highly regulatable brain-specific model, here we report PI3K-dependent mechanisms underlying gyrification of the normally smooth mouse cortex, and hydrocephalus. We demonstrate that a brief embryonic Pik3ca activation was sufficient to drive subtle changes in apical cell adhesion and subcellular Yap translocation, causing focal proliferation and subsequent initiation of the stereotypic 'gyrification sequence', seen in naturally gyrencephalic mammals. Treatment with verteporfin, a nuclear Yap inhibitor, restored apical surface integrity, normalized proliferation, attenuated gyrification and rescued the associated hydrocephalus, highlighting the interrelated role of regulated PI3K-Yap signaling in normal neural-ependymal development. Our data defines apical cell-adhesion as the earliest known substrate for cortical gyrification. In addition, our preclinical results support the testing of Yap-related small-molecule therapeutics for developmental hydrocephalus.

Article and author information

Author details

  1. Achira Roy

    Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6274-0667
  2. Rory M Murphy

    Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Mei Deng

    Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. James W MacDonald

    Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Theo K Bammler

    Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Kimberly A Aldinger

    Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5406-8911
  7. Ian A Glass

    Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Kathleen J Millen

    Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States
    For correspondence
    kathleen.millen@seattlechildrens.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9978-675X

Funding

National Institutes of Health (1R01NS099027)

  • Kathleen J Millen

Seattle Children's Hydrocephalus Research Guild (Seattle Children's Hydrocephalus Research Guild seed fund)

  • Kathleen J Millen

Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD083091)

  • Theo K Bammler

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

Ethics

Animal experimentation: Animal experimentation: All animal experimentation was conducted in accordance with the guidelines laid down by the Institutional Animal Care and Use Committees (IACUC) of Seattle Children's Research Institute, Seattle, WA, USA (protocols 14208 (008) and 14395 (006)).

Reviewing Editor

  1. Francois Guillemot, The Francis Crick Institute, United Kingdom

Publication history

  1. Received: February 13, 2019
  2. Accepted: May 15, 2019
  3. Accepted Manuscript published: May 16, 2019 (version 1)

Copyright

© 2019, Roy 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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