title: Depdc5 knockout rat: A novel model of mTORopathy.
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.
authors.affiliation: INSERM, U1127, ICM, F-75013 Paris, France; CNRS, UMR 7225, ICM, F-75013 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, F-75013 Paris, France.
authors.forename: Elise
authors.initials: E
authors.lastname: Marsan
authors.affiliation: INSERM, U1127, ICM, F-75013 Paris, France; CNRS, UMR 7225, ICM, F-75013 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, F-75013 Paris, France.
authors.forename: Saeko
authors.initials: S
authors.lastname: Ishida
authors.affiliation: INSERM, U1127, ICM, F-75013 Paris, France; CNRS, UMR 7225, ICM, F-75013 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, F-75013 Paris, France.
authors.forename: Adrien
authors.initials: A
authors.lastname: Schramm
authors.affiliation: INSERM, U1127, ICM, F-75013 Paris, France; CNRS, UMR 7225, ICM, F-75013 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, F-75013 Paris, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Weckhuysen
authors.affiliation: INSERM, U1127, ICM, F-75013 Paris, France; CNRS, UMR 7225, ICM, F-75013 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, F-75013 Paris, France.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Muraca
authors.affiliation: INSERM, U1127, ICM, F-75013 Paris, France; CNRS, UMR 7225, ICM, F-75013 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, F-75013 Paris, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Lecas
authors.affiliation: Institut Necker-Enfants Malades, CS 61431, Paris, France; INSERM, U1151, F-75014 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, F-75006 Paris, France.
authors.forename: Ning
authors.initials: N
authors.lastname: Liang
authors.affiliation: Institut Necker-Enfants Malades, CS 61431, Paris, France; INSERM, U1151, F-75014 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, F-75006 Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Treins
authors.affiliation: Institut Necker-Enfants Malades, CS 61431, Paris, France; INSERM, U1151, F-75014 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, F-75006 Paris, France.
authors.forename: Mario
authors.initials: M
authors.lastname: Pende
authors.affiliation: INSERM, U1127, ICM, F-75013 Paris, France; CNRS, UMR 7225, ICM, F-75013 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, F-75013 Paris, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Roussel
authors.affiliation: INSERM, U1127, ICM, F-75013 Paris, France; CNRS, UMR 7225, ICM, F-75013 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, F-75013 Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Le Van Quyen
authors.affiliation: Institute of Experimental Animal Sciences, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan.
authors.forename: Tomoji
authors.initials: T
authors.lastname: Mashimo
authors.affiliation: Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Takehito
authors.initials: T
authors.lastname: Kaneko
authors.affiliation: Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Hiroshima 739-8526, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Hiroshima 739-8526, Japan.
authors.forename: Tetsushi
authors.initials: T
authors.lastname: Sakuma
authors.affiliation: INSERM, U1127, ICM, F-75013 Paris, France; CNRS, UMR 7225, ICM, F-75013 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, F-75013 Paris, France.
authors.forename: Séverine
authors.initials: S
authors.lastname: Mahon
authors.affiliation: INSERM, U1127, ICM, F-75013 Paris, France; CNRS, UMR 7225, ICM, F-75013 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, F-75013 Paris, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Miles
authors.affiliation: INSERM, U1127, ICM, F-75013 Paris, France; CNRS, UMR 7225, ICM, F-75013 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, F-75013 Paris, France; Department of Genetics, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Leguern
authors.affiliation: INSERM, U1127, ICM, F-75013 Paris, France; CNRS, UMR 7225, ICM, F-75013 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, F-75013 Paris, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Charpier
authors.affiliation: INSERM, U1127, ICM, F-75013 Paris, France; CNRS, UMR 7225, ICM, F-75013 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, F-75013 Paris, France; Department of Genetics, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Paris, France. Electronic address: stephanie.baulac@upmc.fr.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Baulac
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002540:Cerebral Cortex / Q000002:abnormalities* / Q000187:drug effects / Q000503:physiopathology; D004195:Disease Models, Animal; D047108:Embryonic Development / Q000187:drug effects / Q000235:genetics*; D005347:Fibroblasts / Q000378:metabolism; D055786:Gene Knockout Techniques; D005838:Genotype; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009474:Neurons / Q000473:pathology / Q000502:physiology; D010766:Phosphorylation; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; D012097:Repressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: DEPDC5; Familial focal epilepsy; Focal cortical dysplasia; Knockout; Rapamycin; mTOR