Knockout of the epilepsy gene Depdc5 in mice causes severe embryonic dysmorphology with hyperactivity of mTORC1 signalling
| Autor: | Melinda N. Tea, Paul Q. Thomas, Laura Stewart, Dale McAninch, Dominique Jackson, Michael G. Ricos, Leanne M. Dibbens, Sandra Piltz, Ruby Dawson, James N. Hughes, Natasha L. Harvey |
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| Přispěvatelé: | Hughes, James, Dawson, Ruby, Tea, Melinda, McAninch, Dale, Piltz, Sandra, Jackson, Dominique, Stewart, Laura, Ricos, Michael G, Dibbens, Leanne M, Harvey, Natasha L, Thomas, Paul |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Heterozygote Pathology medicine.medical_specialty lcsh:Medicine Mutagenesis (molecular biology technique) mTORC1 Mechanistic Target of Rapamycin Complex 1 Biology medicine.disease_cause DEPDC5 mutations Article gene Depdc5 Mice 03 medical and health sciences Epilepsy 0302 clinical medicine Seizures epilepsy in humans medicine Animals Humans lcsh:Science Loss function Mice Knockout Multidisciplinary GTPase-Activating Proteins lcsh:R Brain Fibroblasts medicine.disease Phenotype Embryonic stem cell DEPDC5 3. Good health Disease Models Animal 030104 developmental biology Gene Expression Regulation Multiprotein Complexes Mutation Cancer research lcsh:Q CRISPR-Cas Systems biological phenomena cell phenomena and immunity Carcinogenesis 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Scientific Reports, Vol 7, Iss 1, Pp 1-15 (2017) Scientific Reports |
| ISSN: | 2045-2322 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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