2024
Reply to Pisan et al.: Pathogenicity of inherited TRAF7 mutations in congenital heart disease
Mishra-Gorur K, Barak T, Kaulen L, Henegariu O, Jin S, Aguilera S, Yalbir E, Goles G, Nishimura S, Miyagishima D, Djenoune L, Altinok S, K. D, Viviano S, Prendergast A, Zerillo C, Ozcan K, Baran B, Sencar L, Goc N, Yarman Y, Ercan-encicek A, Bilguvar K, Lifton R, Moliterno J, Louvi A, Yuan S, Deniz E, Brueckner M, Gunel M. Reply to Pisan et al.: Pathogenicity of inherited TRAF7 mutations in congenital heart disease. Proceedings Of The National Academy Of Sciences Of The United States Of America 2024, 121: e2319578121. PMID: 38466853, PMCID: PMC10963000, DOI: 10.1073/pnas.2319578121.Commentaries, Editorials and Letters
2023
Super-enhancer hijacking drives ectopic expression of hedgehog pathway ligands in meningiomas
Youngblood M, Erson-Omay Z, Li C, Najem H, Coșkun S, Tyrtova E, Montejo J, Miyagishima D, Barak T, Nishimura S, Harmancı A, Clark V, Duran D, Huttner A, Avşar T, Bayri Y, Schramm J, Boetto J, Peyre M, Riche M, Goldbrunner R, Amankulor N, Louvi A, Bilgüvar K, Pamir M, Özduman K, Kilic T, Knight J, Simon M, Horbinski C, Kalamarides M, Timmer M, Heimberger A, Mishra-Gorur K, Moliterno J, Yasuno K, Günel M. Super-enhancer hijacking drives ectopic expression of hedgehog pathway ligands in meningiomas. Nature Communications 2023, 14: 6279. PMID: 37805627, PMCID: PMC10560290, DOI: 10.1038/s41467-023-41926-y.Peer-Reviewed Original ResearchMicrocephaly-associated protein WDR62 shuttles from the Golgi apparatus to the spindle poles in human neural progenitors
Dell'Amico C, Salavarria M, Takeo Y, Saotome I, Dell'Anno M, Galimberti M, Pellegrino E, Cattaneo E, Louvi A, Onorati M. Microcephaly-associated protein WDR62 shuttles from the Golgi apparatus to the spindle poles in human neural progenitors. ELife 2023, 12: e81716. PMID: 37272619, PMCID: PMC10241521, DOI: 10.7554/elife.81716.Peer-Reviewed Original ResearchConceptsHuman fetal brain tissueStructural brain abnormalitiesC-terminal truncating mutationsFetal brain tissueEtiology of microcephalySevere neurodevelopmental abnormalitiesStem cellsNeuroepithelial stem cellsHuman neural progenitorsHuman brain developmentBrain abnormalitiesCommon causeNeurodevelopmental abnormalitiesAutosomal recessive primary microcephalyBrain tissueBrain developmentCerebral organoidsMicrocephalyUnaffected parentsTruncating mutationsNeural progenitorsHuman neurodevelopmentAbnormalitiesPleiotropic functionsCritical hubCADASIL mice are characterized by simultaneous metabolic and vascular stress
Wei Z, Li Y, Chen L, Liu H, Yao M, Xu J, Louvi A, Duan W, Lu H. CADASIL mice are characterized by simultaneous metabolic and vascular stress. Proceedings Of The International Society For Magnetic Resonance In Medicine ... Scientific Meeting And Exhibition. 2023 DOI: 10.58530/2023/2649.Peer-Reviewed Original ResearchCADASIL miceMouse modelMouse model of CADASILVascular stressNon-contrast MRI techniqueImpaired cerebrovascular reactivityMicrovascular dysfunctionTherapeutic trialsCerebrovascular reactivityMonogenic conditionsVascular pathologyLacunar strokeMRI techniquesMiceCADASILElevated oxygen consumptionPathologyOxygen consumptionVascular cognitive impairmentCognitive impairmentPleiotropic role of TRAF7 in skull-base meningiomas and congenital heart disease
Mishra-Gorur K, Barak T, Kaulen L, Henegariu O, Jin S, Aguilera S, Yalbir E, Goles G, Nishimura S, Miyagishima D, Djenoune L, Altinok S, K. D, Viviano S, Prendergast A, Zerillo C, Ozcan K, Baran B, Sencar L, Goc N, Yarman Y, Ercan-Sencicek A, Bilguvar K, Lifton R, Moliterno J, Louvi A, Yuan S, Deniz E, Brueckner M, Gunel M. Pleiotropic role of TRAF7 in skull-base meningiomas and congenital heart disease. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2214997120. PMID: 37043537, PMCID: PMC10120005, DOI: 10.1073/pnas.2214997120.Peer-Reviewed Original ResearchConceptsWild-type proteinInherited mutationsCardiac outflow tractDevelopmental heart defectsProtein functionLack ciliaPleiotropic rolesMechanistic convergenceNeural crestCiliary defectsSomatic variantsForebrain meningesCommon originDominant mannerMutationsTRAF7ZebrafishMutantsDisparate pathologiesHeterodimerizationKnockdownGeneticsProteinCiliaCongenital heartAltered Expression of Several Molecular Mediators of Cerebrospinal Fluid Production in Hyp Mice
Kaplan J, Tommasini S, Yao G, Zhu M, Nishimura S, Ghazarian S, Louvi A, Insogna K. Altered Expression of Several Molecular Mediators of Cerebrospinal Fluid Production in Hyp Mice. Journal Of The Endocrine Society 2023, 7: bvad022. PMID: 36819458, PMCID: PMC9936957, DOI: 10.1210/jendso/bvad022.Peer-Reviewed Original Research
2019
The Notch pathway in CNS homeostasis and neurodegeneration
Ho DM, Artavanis‐Tsakonas S, Louvi A. The Notch pathway in CNS homeostasis and neurodegeneration. WIREs Mechanisms Of Disease 2019, 9: e358. PMID: 31502763, DOI: 10.1002/wdev.358.Peer-Reviewed Original ResearchConceptsNervous system developmentCNS homeostasisNotch pathway activityNeurodegenerative diseasesCerebral autosomal dominant arteriopathyAcute brain traumaChronic neurodegenerative conditionsProgressive neurodegenerative diseaseAutosomal dominant arteriopathyCellular contextCentral nervous systemAmyotrophic lateral sclerosisNotch signalsAdult organismNotch activityNotch pathwayNeural developmentMultiple sclerosisAdult neurogenesisBrain traumaPathway activitySubcortical infarctsLateral sclerosisNOTCH3 mutationsHereditary strokeId4 Downstream of Notch2 Maintains Neural Stem Cell Quiescence in the Adult Hippocampus
Zhang R, Boareto M, Engler A, Louvi A, Giachino C, Iber D, Taylor V. Id4 Downstream of Notch2 Maintains Neural Stem Cell Quiescence in the Adult Hippocampus. Cell Reports 2019, 28: 1485-1498.e6. PMID: 31390563, DOI: 10.1016/j.celrep.2019.07.014.Peer-Reviewed Original ResearchConceptsNeural stem cellsDentate gyrusNSC quiescenceAdult mouse hippocampal dentate gyrusNSC proliferationMouse hippocampal dentate gyrusAdult dentate gyrusHippocampal dentate gyrusExpense of neurogenesisNeural stem cell quiescenceId4 knockdownAdult hippocampusNeuron generationId4 expressionNeuronal differentiationCell cycle entryNSC activationMajor effectorStem cell quiescenceNotch2NeurogenesisCell quiescenceStem cellsDownstream targetsNSC maintenance
2018
Cerebrovascular disorders associated with genetic lesions
Karschnia P, Nishimura S, Louvi A. Cerebrovascular disorders associated with genetic lesions. Cellular And Molecular Life Sciences 2018, 76: 283-300. PMID: 30327838, PMCID: PMC6450555, DOI: 10.1007/s00018-018-2934-5.Peer-Reviewed Original ResearchConceptsCerebrovascular disordersGenetic lesionsCerebral blood flowRational therapeutic approachMolecular mechanismsCerebrovascular diseaseMechanistic understandingTherapeutic approachesBlood flowDisease pathogenesisSporadic formsGenomic findingsCurrent knowledgeGenetic formsDisordersLesionsBlood vessel structureWider implicationsPathogenesisAbnormalitiesDiseaseVessel structureNotch2 Signaling Maintains NSC Quiescence in the Murine Ventricular-Subventricular Zone
Engler A, Rolando C, Giachino C, Saotome I, Erni A, Brien C, Zhang R, Zimber-Strobl U, Radtke F, Artavanis-Tsakonas S, Louvi A, Taylor V. Notch2 Signaling Maintains NSC Quiescence in the Murine Ventricular-Subventricular Zone. Cell Reports 2018, 22: 992-1002. PMID: 29386140, DOI: 10.1016/j.celrep.2017.12.094.Peer-Reviewed Original ResearchConceptsV-SVZ neural stem cellsVentricular-subventricular zoneNeural stem cellsQuiescent neural stem cellsRostral migratory streamNew olfactory bulb neuronsNSC quiescenceOlfactory bulb neuronsLoss of Notch2Bulb neuronsNew neuronsAdult forebrainOB lineageAging-like phenotypesMigratory streamNotch2 functionNeuronsNotch2Canonical Notch signalingNeurogenesisStem cellsNotch signalingCell cycleForebrainQuiescence
2017
Combined HMG-COA reductase and prenylation inhibition in treatment of CCM
Nishimura S, Mishra-Gorur K, Park J, Surovtseva YV, Sebti SM, Levchenko A, Louvi A, Gunel M. Combined HMG-COA reductase and prenylation inhibition in treatment of CCM. Proceedings Of The National Academy Of Sciences Of The United States Of America 2017, 114: 5503-5508. PMID: 28500274, PMCID: PMC5448170, DOI: 10.1073/pnas.1702942114.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAstrocytesDiphosphonatesDrosophilaDrug Evaluation, PreclinicalDrug Therapy, CombinationEndothelial CellsFatty Acids, MonounsaturatedFemaleFluvastatinHemangioma, Cavernous, Central Nervous SystemHigh-Throughput Screening AssaysHydroxymethylglutaryl-CoA Reductase InhibitorsImidazolesIndolesMaleMAP Kinase Signaling SystemMicePregnancyProtein PrenylationZoledronic AcidConceptsCerebral cavernous malformationsTreatment of CCMsCommon vascular anomaliesPotential pharmacological treatment optionsFocal neurological deficitsPharmacological treatment optionsCCM diseaseAcute mouse modelCentral nervous systemNeurological deficitsHemorrhagic strokePharmacological therapyLesion burdenVascular deficitsSymptomatic lesionsCombination therapyTreatment optionsVascular anomaliesGlial cellsCavernous malformationsMouse modelPrimary astrocytesNervous systemDrug AdministrationSustained inhibitionDisruptions in asymmetric centrosome inheritance and WDR62-Aurora kinase B interactions in primary microcephaly
Sgourdou P, Mishra-Gorur K, Saotome I, Henagariu O, Tuysuz B, Campos C, Ishigame K, Giannikou K, Quon JL, Sestan N, Caglayan AO, Gunel M, Louvi A. Disruptions in asymmetric centrosome inheritance and WDR62-Aurora kinase B interactions in primary microcephaly. Scientific Reports 2017, 7: 43708. PMID: 28272472, PMCID: PMC5341122, DOI: 10.1038/srep43708.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAurora Kinase BBrainCell CycleCell Cycle ProteinsCell DifferentiationCell ProliferationCentrosomeConsanguinityDisease Models, AnimalEpistasis, GeneticFluorescent Antibody TechniqueGene ExpressionHumansInheritance PatternsMaleMiceMice, KnockoutMicrocephalyMutationNerve Tissue ProteinsNeural Stem CellsPedigreeWhole Genome SequencingConceptsChromosome passenger complexPatient-derived fibroblastsCentrosome inheritanceNeocortical progenitorsDisease-associated mutant formsSpindle pole localizationAurora kinase BPassenger complexMitotic progressionMouse orthologDiverse functionsMutant formsWD repeat domain 62Key regulatorCPC componentsKinase BPole localizationPrimary microcephalyLate neurogenesisRecessive mutationsNeuronal differentiationWDR62Severe brain malformationsReduced proliferationNeocortical development
2016
B-Cell Depletion Reduces the Maturation of Cerebral Cavernous Malformations in Murine Models
Shi C, Shenkar R, Zeineddine HA, Girard R, Fam MD, Austin C, Moore T, Lightle R, Zhang L, Wu M, Cao Y, Gunel M, Louvi A, Rorrer A, Gallione C, Marchuk DA, Awad IA. B-Cell Depletion Reduces the Maturation of Cerebral Cavernous Malformations in Murine Models. Journal Of Neuroimmune Pharmacology 2016, 11: 369-377. PMID: 27086141, PMCID: PMC6746226, DOI: 10.1007/s11481-016-9670-0.Peer-Reviewed Original ResearchConceptsB-cell depletionCerebral cavernous malformationsCCM lesionsB cellsImmune responseMurine modelCavernous malformationsIron depositionB cell clonal expansionInflammatory cell infiltrationStage 2 lesionsProgression of lesionsBlood degradation productsCommon vascular malformationsPotential therapeutic agentROCK activityRho-kinase activityUntreated miceAntigenic triggerCell depletionCell infiltrationVascular malformationsImmune complexesTherapeutic benefitLesion genesisNotch1 and Notch2 receptors regulate mouse and human gastric antral epithelial cell homoeostasis
Gifford GB, Demitrack ES, Keeley TM, Tam A, La Cunza N, Dedhia PH, Spence JR, Simeone DM, Saotome I, Louvi A, Siebel CW, Samuelson LC. Notch1 and Notch2 receptors regulate mouse and human gastric antral epithelial cell homoeostasis. Gut 2016, 66: 1001. PMID: 26933171, PMCID: PMC5009003, DOI: 10.1136/gutjnl-2015-310811.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodies, Monoclonal, HumanizedApoptosisCell DifferentiationCell ProliferationCells, CulturedDibenzazepinesEpithelial CellsFemaleGastric MucosaGene ExpressionHomeostasisHumansMaleMiceMice, Inbred C57BLMice, TransgenicOrganoidsPyloric AntrumReceptor, Notch1Receptor, Notch2Receptors, G-Protein-CoupledSignal TransductionStem CellsConceptsEpithelial cell homeostasisCell homeostasisNotch receptorsNotch inhibitor dibenzazepineGlobal Notch inhibitionStem cellsAntral stem cellsHuman antral glandsAnalysis of miceNotch pathway receptorsLgr5 stem cellsCellular differentiationNotch signalingNotch2 receptorMolecular approachesPathway receptorsNotch pathway inhibitionHuman organoidsEpithelial cell proliferationNotch inhibitionInhibition of Notch1Notch inhibitorsOrganoid growthCell proliferationNotch2
2015
Integrated genomic characterization of IDH1-mutant glioma malignant progression
Bai H, Harmancı AS, Erson-Omay EZ, Li J, Coşkun S, Simon M, Krischek B, Özduman K, Omay SB, Sorensen EA, Turcan Ş, Bakırcığlu M, Carrión-Grant G, Murray PB, Clark VE, Ercan-Sencicek AG, Knight J, Sencar L, Altınok S, Kaulen LD, Gülez B, Timmer M, Schramm J, Mishra-Gorur K, Henegariu O, Moliterno J, Louvi A, Chan TA, Tannheimer SL, Pamir MN, Vortmeyer AO, Bilguvar K, Yasuno K, Günel M. Integrated genomic characterization of IDH1-mutant glioma malignant progression. Nature Genetics 2015, 48: 59-66. PMID: 26618343, PMCID: PMC4829945, DOI: 10.1038/ng.3457.Peer-Reviewed Original ResearchConceptsDevelopmental transcription factorsActivation of MYCMalignant progressionGenomic approachesPI3K pathwayGlioma malignant progressionEpigenetic silencingIDH1 mutant gliomasTranscription factorsIntegrated genomic characterizationGenomic characterizationRTK-RASOncogenic pathwaysK pathwayClonal expansionPathwaySilencingMYCProgressionStructure and vascular function of MEKK3–cerebral cavernous malformations 2 complex
Fisher OS, Deng H, Liu D, Zhang Y, Wei R, Deng Y, Zhang F, Louvi A, Turk BE, Boggon TJ, Su B. Structure and vascular function of MEKK3–cerebral cavernous malformations 2 complex. Nature Communications 2015, 6: 7937. PMID: 26235885, PMCID: PMC4526114, DOI: 10.1038/ncomms8937.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnimals, NewbornBlood VesselsCapillary PermeabilityCerebrovascular CirculationCrystallizationHemangioma, Cavernous, Central Nervous SystemIntracranial HemorrhagesMAP Kinase Kinase Kinase 3MiceMice, KnockoutMicrofilament ProteinsNeovascularization, PhysiologicRho GTP-Binding ProteinsRho-Associated KinasesSignal TransductionFunctional Synergy between Cholecystokinin Receptors CCKAR and CCKBR in Mammalian Brain Development
Nishimura S, Bilgüvar K, Ishigame K, Sestan N, Günel M, Louvi A. Functional Synergy between Cholecystokinin Receptors CCKAR and CCKBR in Mammalian Brain Development. PLOS ONE 2015, 10: e0124295. PMID: 25875176, PMCID: PMC4398320, DOI: 10.1371/journal.pone.0124295.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnimals, NewbornBone Morphogenetic Protein 7Cell MovementChemokine CXCL12CholecystokininCorpus CallosumEmbryo, MammalianGene Expression ProfilingGene Expression Regulation, DevelopmentalHomozygoteHumansInterneuronsMiceMice, KnockoutMidline Thalamic NucleiMutationNeocortexNeuropilin-2Receptor, Cholecystokinin AReceptor, Cholecystokinin BReceptors, N-Methyl-D-AspartateSignal TransductionTranscriptomeConceptsCCK receptorsBrain developmentMammalian neocortical developmentCentral nervous systemCortical interneuron migrationHomozygous mutant miceMammalian brain developmentPeripheral organsReceptor lossCorpus callosumCortical developmentPostnatal brainAbundant neuropeptideNervous systemInterneuron migrationMutant miceEmbryonic neocortexNeocortical developmentReceptorsPeptide hormonesG proteinsCholecystokininReciprocal expressionCCKBRBrainMutations in KATNB1 Cause Complex Cerebral Malformations by Disrupting Asymmetrically Dividing Neural Progenitors
Mishra-Gorur K, Çağlayan AO, Schaffer AE, Chabu C, Henegariu O, Vonhoff F, Akgümüş GT, Nishimura S, Han W, Tu S, Baran B, Gümüş H, Dilber C, Zaki MS, Hossni HAA, Rivière JB, Kayserili H, Spencer EG, Rosti RÖ, Schroth J, Per H, Çağlar C, Çağlar Ç, Dölen D, Baranoski JF, Kumandaş S, Minja FJ, Erson-Omay EZ, Mane SM, Lifton RP, Xu T, Keshishian H, Dobyns WB, C. NC, Šestan N, Louvi A, Bilgüvar K, Yasuno K, Gleeson JG, Günel M. Mutations in KATNB1 Cause Complex Cerebral Malformations by Disrupting Asymmetrically Dividing Neural Progenitors. Neuron 2015, 85: 228. PMID: 29654772, DOI: 10.1016/j.neuron.2014.12.046.Peer-Reviewed Original Research
2014
Mutations in KATNB1 Cause Complex Cerebral Malformations by Disrupting Asymmetrically Dividing Neural Progenitors
Mishra-Gorur K, Çağlayan AO, Schaffer AE, Chabu C, Henegariu O, Vonhoff F, Akgümüş GT, Nishimura S, Han W, Tu S, Baran B, Gümüş H, Dilber C, Zaki MS, Hossni HA, Rivière JB, Kayserili H, Spencer EG, Rosti RÖ, Schroth J, Per H, Çağlar C, Çağlar Ç, Dölen D, Baranoski JF, Kumandaş S, Minja FJ, Erson-Omay EZ, Mane SM, Lifton RP, Xu T, Keshishian H, Dobyns WB, C. N, Šestan N, Louvi A, Bilgüvar K, Yasuno K, Gleeson JG, Günel M. Mutations in KATNB1 Cause Complex Cerebral Malformations by Disrupting Asymmetrically Dividing Neural Progenitors. Neuron 2014, 84: 1226-1239. PMID: 25521378, PMCID: PMC5024344, DOI: 10.1016/j.neuron.2014.12.014.Peer-Reviewed Original ResearchConceptsComplex cerebral malformationsCerebral cortical malformationsMicrotubule-severing enzyme kataninExome sequencing analysisMitotic spindle formationDrosophila optic lobeCerebral malformationsPatient-derived fibroblastsCell cycle progression delayCortical malformationsMotor neuronsComplex malformationsMicrotubule-associated proteinsCortical developmentReduced cell numberOptic lobeRegulatory subunitBrain developmentCatalytic subunitDeleterious mutationsSpindle formationSupernumerary centrosomesArborization defectsMalformationsHuman phenotypesCcm3, a gene associated with cerebral cavernous malformations, is required for neuronal migration
Louvi A, Nishimura S, Günel M. Ccm3, a gene associated with cerebral cavernous malformations, is required for neuronal migration. Journal Of Cell Science 2014, 127: e1-e1. DOI: 10.1242/jcs.152207.Peer-Reviewed Original Research