RGD Reference Report - Depdc5 knockout rat: A novel model of mTORopathy. - Rat Genome Database

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Depdc5 knockout rat: A novel model of mTORopathy.

Authors: Marsan, Elise  Ishida, Saeko  Schramm, Adrien  Weckhuysen, Sarah  Muraca, Giuseppe  Lecas, Sarah  Liang, Ning  Treins, Caroline  Pende, Mario  Roussel, Delphine  Le Van Quyen, Michel  Mashimo, Tomoji  Kaneko, Takehito  Yamamoto, Takashi  Sakuma, Tetsushi  Mahon, Séverine  Miles, Richard  Leguern, Eric  Charpier, Stéphane  Baulac, Stéphanie 
Citation: Marsan E, etal., Neurobiol Dis. 2016 May;89:180-9. doi: 10.1016/j.nbd.2016.02.010. Epub 2016 Feb 9.
RGD ID: 11573213
Pubmed: (View Article at PubMed) PMID:26873552
DOI: Full-text: DOI:10.1016/j.nbd.2016.02.010

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.

Annotation

Phenotype Annotations    
Objects Annotated

Genes (Rattus norvegicus)
Depdc5  (DEP domain containing 5, GATOR1 subcomplex subunit)
Depdc5em1Kyo  (DEP domain containing 5, GATOR1 subcomplex subunit; TALEN induced mutant1, Kyo)
Depdc5em2Kyo  (DEP domain containing 5, GATOR1 subcomplex subunit; TALEN induced mutant2, Kyo)


Additional Information