1. Human Biology and Medicine
  2. Neuroscience
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Mouse models of human PIK3CA-related brain overgrowth have acutely treatable epilepsy

  1. Achira Roy
  2. Jonathan Skibo
  3. Franck Kalume
  4. Jing Ni
  5. Sherri Rankin
  6. Yiling Lu
  7. William B Dobyns
  8. Gordon B Mills
  9. Jean J Zhao
  10. Suzanne J Baker
  11. Kathleen J Millen  Is a corresponding author
  1. Seattle Children's Research Institute, United States
  2. Dana Farber Cancer Institute, United States
  3. St. Jude Children's Research Hospital, United States
  4. The University of Texas MD Anderson Cancer Center, United States
Research Article
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Cite this article as: eLife 2015;4:e12703 doi: 10.7554/eLife.12703

Abstract

Mutations in the catalytic subunit of phosphoinositide 3-kinase (PIK3CA) and other PI3K-AKT pathway components have been associated with cancer and a wide spectrum of brain and body overgrowth. In the brain, the phenotypic spectrum of PIK3CA-related segmental overgrowth includes bilateral dysplastic megalencephaly, hemimegalencephaly and focal cortical dysplasia, the most common cause of intractable pediatric epilepsy. We generated mouse models expressing the most common activating Pik3ca mutations (H1047R and E545K) in developing neural progenitors. These accurately recapitulate all the key human pathological features including brain enlargement, cortical malformation, hydrocephalus and epilepsy, with phenotypic severity dependent on the mutant allele and its time of activation. Underlying mechanisms include increased proliferation, cell size and altered white matter. Notably, we demonstrate that acute 1hour-suppression of PI3K signaling despite the ongoing presence of dysplasia has dramatic anti-epileptic benefit. Thus PI3K inhibitors offer a promising new avenue for effective anti-epileptic therapy for intractable pediatric epilepsy patients.

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.
  2. Jonathan Skibo

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

    Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Jing Ni

    Department of Cancer biology, Dana Farber Cancer Institute, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Sherri Rankin

    Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Yiling Lu

    The University of Texas MD Anderson Cancer Center, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. William B Dobyns

    Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Gordon B Mills

    The University of Texas MD Anderson Cancer Center, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Jean J Zhao

    Department of Cancer Biology, Dana Farber Cancer Institute, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Suzanne J Baker

    Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. 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.

Ethics

Animal experimentation: All animal experimentation done in this study was done in accordance with the guidelines laid down by the Institutional Animal Care and Use Committees (IACUC) of Seattle Children's Research Institute, Seattle, WA (protocol 14208), St. Jude Children's Research Hospital, Memphis, TN (protocol 278), Dana Farber Cancer Institute, Boston, MA (protocol 06-034).

Reviewing Editor

  1. Sean J Morrison, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, United States

Publication history

  1. Received: October 29, 2015
  2. Accepted: November 26, 2015
  3. Accepted Manuscript published: December 3, 2015 (version 1)
  4. Version of Record published: January 27, 2016 (version 2)

Copyright

© 2015, 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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