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

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.

Data availability

RNA-seq data have been deposited in the NCBI Gene Expression Omnibus under the accession code GSE127896. Related analysed data are provided in Figure 6 - Source Data 1 and Figure 6 - Source Data 2 for Figure 6 and Figure 6 - figure supplements 2 and 3

The following data sets were generated
The following previously published data sets were used

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.

Reviewing Editor

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

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)).

Version history

  1. Received: February 13, 2019
  2. Accepted: May 15, 2019
  3. Accepted Manuscript published: May 16, 2019 (version 1)
  4. Version of Record published: May 31, 2019 (version 2)

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.

Metrics

  • 2,906
    Page views
  • 387
    Downloads
  • 19
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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
(2019)
PI3K-Yap activity drives cortical gyrification and hydrocephalus in mice
eLife 8:e45961.
https://doi.org/10.7554/eLife.45961

Share this article

https://doi.org/10.7554/eLife.45961

Further reading

    1. Neuroscience
    Harry Clark, Matthew F Nolan
    Research Article

    Grid firing fields have been proposed as a neural substrate for spatial localisation in general or for path integration in particular. To distinguish these possibilities, we investigate firing of grid and non-grid cells in the mouse medial entorhinal cortex during a location memory task. We find that grid firing can either be anchored to the task environment, or can encode distance travelled independently of the task reference frame. Anchoring varied between and within sessions, while spatial firing of non-grid cells was either coherent with the grid population, or was stably anchored to the task environment. We took advantage of the variability in task-anchoring to evaluate whether and when encoding of location by grid cells might contribute to behaviour. We find that when reward location is indicated by a visual cue, performance is similar regardless of whether grid cells are task-anchored or not, arguing against a role for grid representations when location cues are available. By contrast, in the absence of the visual cue, performance was enhanced when grid cells were anchored to the task environment. Our results suggest that anchoring of grid cells to task reference frames selectively enhances performance when path integration is required.

    1. Neuroscience
    Kiwamu Kudo, Kamalini G Ranasinghe ... Srikantan S Nagarajan
    Research Article

    Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β and misfolded tau proteins causing synaptic dysfunction, and progressive neurodegeneration and cognitive decline. Altered neural oscillations have been consistently demonstrated in AD. However, the trajectories of abnormal neural oscillations in AD progression and their relationship to neurodegeneration and cognitive decline are unknown. Here, we deployed robust event-based sequencing models (EBMs) to investigate the trajectories of long-range and local neural synchrony across AD stages, estimated from resting-state magnetoencephalography. The increases in neural synchrony in the delta-theta band and the decreases in the alpha and beta bands showed progressive changes throughout the stages of the EBM. Decreases in alpha and beta band synchrony preceded both neurodegeneration and cognitive decline, indicating that frequency-specific neuronal synchrony abnormalities are early manifestations of AD pathophysiology. The long-range synchrony effects were greater than the local synchrony, indicating a greater sensitivity of connectivity metrics involving multiple regions of the brain. These results demonstrate the evolution of functional neuronal deficits along the sequence of AD progression.