Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/109257
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Type: | Journal article |
Title: | Knockout of the epilepsy gene Depdc5 in mice causes severe embryonic dysmorphology with hyperactivity of mTORC1 signalling |
Author: | Hughes, J. Dawson, R. Tea, M. McAninch, D. Piltz, S. Jackson, D. Stewart, L. Ricos, M. Dibbens, L. Harvey, N. Thomas, P. |
Citation: | Scientific Reports, 2017; 7(1):12618-1-12618-15 |
Publisher: | Nature Publishing Group |
Issue Date: | 2017 |
ISSN: | 2045-2322 2045-2322 |
Statement of Responsibility: | James Hughes, Ruby Dawson, Melinda Tea, Dale McAninch, Sandra Piltz, Dominique Jackson, Laura Stewart, Michael G. Ricos, Leanne M. Dibbens, Natasha L. Harvey and Paul Thomas |
Abstract: | DEPDC5 mutations have recently been shown to cause epilepsy in humans. Evidence from in vitro studies has implicated DEPDC5 as a negative regulator of mTORC1 during amino acid insufficiency as part of the GATOR1 complex. To investigate the role of DEPDC5 in vivo we generated a null mouse model using targeted CRISPR mutagenesis. Depdc5 homozygotes display severe phenotypic defects between 12.5-15.5 dpc, including hypotrophy, anaemia, oedema, and cranial dysmorphology as well as blood and lymphatic vascular defects. mTORC1 hyperactivity was observed in the brain of knockout embryos and in fibroblasts and neurospheres isolated from knockout embryos and cultured in nutrient deprived conditions. Heterozygous mice appeared to be normal and we found no evidence of increased susceptibility to seizures or tumorigenesis. Together, these data support mTORC1 hyperactivation as the likely pathogenic mechanism that underpins DEPDC5 loss of function in humans and highlights the potential utility of mTORC1 inhibitors in the treatment of DEPDC5-associated epilepsy. |
Keywords: | Brain Fibroblasts Animals Mice, Knockout Humans Mice Epilepsy Seizures Disease Models, Animal Multiprotein Complexes GTPase-Activating Proteins Signal Transduction Gene Expression Regulation Heterozygote Mutation CRISPR-Cas Systems Mechanistic Target of Rapamycin Complex 1 |
Description: | Published online: 03 October 2017 |
Rights: | © The Author(s) 2017. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
DOI: | 10.1038/s41598-017-12574-2 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/628952 http://purl.org/au-research/grants/nhmrc/1083690 http://purl.org/au-research/grants/arc/FT130101254 http://purl.org/au-research/grants/nhmrc/1104718 |
Published version: | http://dx.doi.org/10.1038/s41598-017-12574-2 |
Appears in Collections: | Aurora harvest 3 Paediatrics publications |
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File | Description | Size | Format | |
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hdl_109257.pdf | Published version | 5.15 MB | Adobe PDF | View/Open |
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