PI3K-Yap activity drives cortical gyrification and hydrocephalus in mice
- Seattle Children's Research Institute, United States
- 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
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PI3K-Yap activity drives cortical gyrification and hydrocephalus in miceNCBI Gene Expression Omnibus, GSE127896.
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Sharp changes in gene expression levels along germinal layers distinguish the development of gyrencephalyNCBI Gene Expression Omnibus, GSE60687.
Article and author information
Author details
Kimberly A Aldinger
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
- 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
- Received: February 13, 2019
- Accepted: May 15, 2019
- Accepted Manuscript published: May 16, 2019 (version 1)
- 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.
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PI3K-Yap activity drives cortical gyrification and hydrocephalus in mice
eLife 8:e45961.
https://doi.org/10.7554/eLife.45961
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