Mouse models of human PIK3CA-related brain overgrowth have acutely treatable epilepsy

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...

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Main Authors: Achira Roy, Jonathan Skibo, Franck Kalume, Jing Ni, Sherri Rankin, Yiling Lu, William B Dobyns, Gordon B Mills, Jean J Zhao, Suzanne J Baker, Kathleen J Millen
Format: Article
Language:English
Published: eLife Sciences Publications Ltd 2015-12-01
Series:eLife
Subjects:
Online Access:https://elifesciences.org/articles/12703
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author Achira Roy
Jonathan Skibo
Franck Kalume
Jing Ni
Sherri Rankin
Yiling Lu
William B Dobyns
Gordon B Mills
Jean J Zhao
Suzanne J Baker
Kathleen J Millen
author_facet Achira Roy
Jonathan Skibo
Franck Kalume
Jing Ni
Sherri Rankin
Yiling Lu
William B Dobyns
Gordon B Mills
Jean J Zhao
Suzanne J Baker
Kathleen J Millen
author_sort Achira Roy
collection DOAJ
description 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 1 hr-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.
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spelling doaj.art-8b73c5ef06e44f5fb30f8bcd73579e052022-12-22T03:52:53ZengeLife Sciences Publications LtdeLife2050-084X2015-12-01410.7554/eLife.12703Mouse models of human PIK3CA-related brain overgrowth have acutely treatable epilepsyAchira Roy0Jonathan Skibo1Franck Kalume2Jing Ni3Sherri Rankin4Yiling Lu5William B Dobyns6Gordon B Mills7Jean J Zhao8Suzanne J Baker9Kathleen J Millen10Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United StatesCenter for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United StatesCenter for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United StatesDepartment of Cancer Biology, Dana Farber Cancer Institute, Boston, United StatesDepartment of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, United StatesThe University of Texas MD Anderson Cancer Center, Houston, United StatesCenter for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United StatesThe University of Texas MD Anderson Cancer Center, Houston, United StatesDepartment of Cancer Biology, Dana Farber Cancer Institute, Boston, United StatesDepartment of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, United StatesCenter for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United StatesMutations 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 1 hr-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.https://elifesciences.org/articles/12703PI3Kmegalencephalymouse modelsepilepsyBKM120cortical dysplasia
spellingShingle Achira Roy
Jonathan Skibo
Franck Kalume
Jing Ni
Sherri Rankin
Yiling Lu
William B Dobyns
Gordon B Mills
Jean J Zhao
Suzanne J Baker
Kathleen J Millen
Mouse models of human PIK3CA-related brain overgrowth have acutely treatable epilepsy
eLife
PI3K
megalencephaly
mouse models
epilepsy
BKM120
cortical dysplasia
title Mouse models of human PIK3CA-related brain overgrowth have acutely treatable epilepsy
title_full Mouse models of human PIK3CA-related brain overgrowth have acutely treatable epilepsy
title_fullStr Mouse models of human PIK3CA-related brain overgrowth have acutely treatable epilepsy
title_full_unstemmed Mouse models of human PIK3CA-related brain overgrowth have acutely treatable epilepsy
title_short Mouse models of human PIK3CA-related brain overgrowth have acutely treatable epilepsy
title_sort mouse models of human pik3ca related brain overgrowth have acutely treatable epilepsy
topic PI3K
megalencephaly
mouse models
epilepsy
BKM120
cortical dysplasia
url https://elifesciences.org/articles/12703
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