RRC ID 37537
Author Marsan E, Ishida S, Schramm A, Weckhuysen S, Muraca G, Lecas S, Liang N, Treins C, Pende M, Roussel D, Le Van Quyen M, Mashimo T, Kaneko T, Yamamoto T, Sakuma T, Mahon S, Miles R, Leguern E, Charpier S, Baulac S.
Title Depdc5 knockout rat: A novel model of mTORopathy.
Journal Neurobiol. Dis.
Abstract DEP-domain containing 5 (DEPDC5), encoding a repressor of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway, has recently emerged as a major gene mutated in familial focal epilepsies and focal cortical dysplasia. Here we established a global knockout rat using TALEN technology to investigate in vivo the impact of Depdc5-deficiency. Homozygous Depdc5(-/-) embryos died from embryonic day 14.5 due to a global growth delay. Constitutive mTORC1 hyperactivation was evidenced in the brains and in cultured fibroblasts of Depdc5(-/-) embryos, as reflected by enhanced phosphorylation of its downstream effectors S6K1 and rpS6. Consistently, prenatal treatment with mTORC1 inhibitor rapamycin rescued the phenotype of Depdc5(-/-) embryos. Heterozygous Depdc5(+/-) rats developed normally and exhibited no spontaneous electroclinical seizures, but had altered cortical neuron excitability and firing patterns. Depdc5(+/-) rats displayed cortical cytomegalic dysmorphic neurons and balloon-like cells strongly expressing phosphorylated rpS6, indicative of mTORC1 upregulation, and not observed after prenatal rapamycin treatment. These neuropathological abnormalities are reminiscent of the hallmark brain pathology of human focal cortical dysplasia. Altogether, Depdc5 knockout rats exhibit multiple features of rodent models of mTORopathies, and thus, stand as a relevant model to study their underlying pathogenic mechanisms.
Volume 89
Pages 180-9
Published 2016-5
DOI 10.1016/j.nbd.2016.02.010
PII S0969-9961(16)30031-6
PMID 26873552
MeSH Animals Animals, Genetically Modified Cerebral Cortex / abnormalities* Cerebral Cortex / drug effects Cerebral Cortex / physiopathology Disease Models, Animal* Embryonic Development / drug effects Embryonic Development / genetics* Fibroblasts / metabolism Gene Knockout Techniques Genotype Mechanistic Target of Rapamycin Complex 1 Multiprotein Complexes / antagonists & inhibitors Multiprotein Complexes / metabolism* Neurons / pathology Neurons / physiology Phosphorylation Rats Rats, Inbred F344 Rats, Wistar Repressor Proteins / genetics* Repressor Proteins / metabolism Repressor Proteins / physiology* Signal Transduction / drug effects Sirolimus / administration & dosage TOR Serine-Threonine Kinases / antagonists & inhibitors TOR Serine-Threonine Kinases / metabolism*
IF 5.227
Times Cited 7
Rats F344-Depdc5em1kyo F344-Depdc5em2kyo