2019
Id4 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
Notch2 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
Structure 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 expressionCCKBRBrain
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. Development 2014, 141: 1404-1415. PMID: 24595293, PMCID: PMC3943187, DOI: 10.1242/dev.093526.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosis Regulatory ProteinsCell MovementCell ProliferationCyclin-Dependent Kinase 5FemaleHemangioma, Cavernous, Central Nervous SystemIntracellular Signaling Peptides and ProteinsMiceMice, KnockoutMice, TransgenicNeocortexNeural Stem CellsNeurogliaPregnancyRho GTP-Binding ProteinsRhoA GTP-Binding ProteinSignal TransductionConceptsCerebral cavernous malformation 3Neuronal migrationCerebral cavernous malformationsRadial glia progenitorsCell non-autonomous functionCerebrovascular disordersPyramidal neuronsCortical plateLaminar positioningSubventricular zoneCortical developmentCavernous malformationsRadial gliaLoss of functionNascent neuronsNeuronal morphologySevere malformationsGlia progenitorsNeural progenitorsNeuronsNon-autonomous functionsMalformationsRhoA pathwayPossible interactionsGlia
2011
Notch Lineages and Activity in Intestinal Stem Cells Determined by a New Set of Knock-In Mice
Fre S, Hannezo E, Sale S, Huyghe M, Lafkas D, Kissel H, Louvi A, Greve J, Louvard D, Artavanis-Tsakonas S. Notch Lineages and Activity in Intestinal Stem Cells Determined by a New Set of Knock-In Mice. PLOS ONE 2011, 6: e25785. PMID: 21991352, PMCID: PMC3185035, DOI: 10.1371/journal.pone.0025785.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBasic Helix-Loop-Helix Transcription FactorsCell DifferentiationCell LineageClone CellsEnterocytesGene Knock-In TechniquesGene TargetingHomeodomain ProteinsIntegrasesIntestinesKineticsMiceMice, Inbred C57BLMice, TransgenicMicrovilliMultipotent Stem CellsReceptors, NotchSequence Homology, Amino AcidSignal TransductionStem CellsTranscription Factor HES-1Transcription, GeneticRecessive LAMC3 mutations cause malformations of occipital cortical development
Barak T, Kwan KY, Louvi A, Demirbilek V, Saygı S, Tüysüz B, Choi M, Boyacı H, Doerschner K, Zhu Y, Kaymakçalan H, Yılmaz S, Bakırcıoğlu M, Çağlayan A, Öztürk A, Yasuno K, Brunken WJ, Atalar E, Yalçınkaya C, Dinçer A, Bronen RA, Mane S, Özçelik T, Lifton RP, Šestan N, Bilgüvar K, Günel M. Recessive LAMC3 mutations cause malformations of occipital cortical development. Nature Genetics 2011, 43: 590-594. PMID: 21572413, PMCID: PMC3329933, DOI: 10.1038/ng.836.Peer-Reviewed Original ResearchHypomorphic Notch 3 alleles link Notch signaling to ischemic cerebral small-vessel disease
Arboleda-Velasquez JF, Manent J, Lee JH, Tikka S, Ospina C, Vanderburg CR, Frosch MP, Rodríguez-Falcón M, Villen J, Gygi S, Lopera F, Kalimo H, Moskowitz MA, Ayata C, Louvi A, Artavanis-Tsakonas S. Hypomorphic Notch 3 alleles link Notch signaling to ischemic cerebral small-vessel disease. Proceedings Of The National Academy Of Sciences Of The United States Of America 2011, 108: e128-e135. PMID: 21555590, PMCID: PMC3102344, DOI: 10.1073/pnas.1101964108.Peer-Reviewed Original ResearchConceptsSmall vessel diseaseIschemic cerebral small-vessel diseaseCerebral small vessel diseaseGranular osmiophilic materialMouse modelCerebral autosomal dominant arteriopathySmooth muscle cell degenerationBrain vessel pathologyPrevalent human conditionVascular smooth muscle cellsNotch 3 mutationPostmortem human tissueAutosomal dominant arteriopathyTransgenic mouse modelIschemic stroke susceptibilityAge-dependent phenotypeMuscle cell degenerationSmooth muscle cellsNotch-3 receptorCommon monogenic causeIschemic strokeVascular dementiaSubcortical infarctsReceptor activity assaysHuman brain vesselsLoss of cerebral cavernous malformation 3 (Ccm3) in neuroglia leads to CCM and vascular pathology
Louvi A, Chen L, Two AM, Zhang H, Min W, Günel M. Loss of cerebral cavernous malformation 3 (Ccm3) in neuroglia leads to CCM and vascular pathology. Proceedings Of The National Academy Of Sciences Of The United States Of America 2011, 108: 3737-3742. PMID: 21321212, PMCID: PMC3048113, DOI: 10.1073/pnas.1012617108.Peer-Reviewed Original ResearchConceptsNeural cellsCerebral cavernous malformationsCell-nonautonomous mechanismsPathogenesis of CCMsRho GTPase signalingCell-autonomous mechanismsCell-autonomous roleCerebral cavernous malformation 3Cell death 10Central nervous systemConditional mouse mutantsNonautonomous functionsCytoskeletal remodelingRNA sequencingCCM3/Mouse mutantsNeurovascular unitNonautonomous mechanismsProper developmentVascular lesionsGene 1Function mutationsNervous systemAutonomous mechanismsLate functions
2010
Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations
Bilgüvar K, Öztürk A, Louvi A, Kwan KY, Choi M, Tatlı B, Yalnızoğlu D, Tüysüz B, Çağlayan A, Gökben S, Kaymakçalan H, Barak T, Bakırcıoğlu M, Yasuno K, Ho W, Sanders S, Zhu Y, Yılmaz S, Dinçer A, Johnson MH, Bronen RA, Koçer N, Per H, Mane S, Pamir MN, Yalçınkaya C, Kumandaş S, Topçu M, Özmen M, Šestan N, Lifton RP, State MW, Günel M. Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations. Nature 2010, 467: 207-210. PMID: 20729831, PMCID: PMC3129007, DOI: 10.1038/nature09327.Peer-Reviewed Original ResearchConceptsAbnormal cortical developmentWD repeat domain 62 (WDR62) geneSevere brain malformationsWhole-exome sequencingBrain abnormalitiesBrain malformationsCortical developmentMolecular pathogenesisCerebellar hypoplasiaWDR62 mutationsEmbryonic neurogenesisDiagnostic classificationMicrocephaly genesSmall family sizeGenetic heterogeneityWide spectrumRecessive mutationsPachygyriaPathogenesisHypoplasiaNeocortexNeurogenesisAbnormalitiesMalformationsMutations
2008
Developmentally regulated and evolutionarily conserved expression of SLITRK1 in brain circuits implicated in Tourette syndrome
Stillman AA, Krsnik Ž, Sun J, Rašin M, State MW, šestan N, Louvi A. Developmentally regulated and evolutionarily conserved expression of SLITRK1 in brain circuits implicated in Tourette syndrome. The Journal Of Comparative Neurology 2008, 513: 21-37. PMID: 19105198, PMCID: PMC3292218, DOI: 10.1002/cne.21919.Peer-Reviewed Original ResearchConceptsCorticostriatal-thalamocortical circuitsSingle-pass transmembrane proteinTourette syndromeEtiology of TSRare sequence variantsTransmembrane proteinSLITRK1Expression patternsCortical pyramidal neuronsCytoplasmic vesiclesDevelopmental expressionMember 1 geneSequence variantsAxonal repulsionSlit familyDendritic patterningDirect output pathwayCholinergic interneuronsPyramidal neuronsProjection neuronsStriatal expressionMotor ticsSomatodendritic compartmentDevelopmental neuropsychiatric disordersPatch compartmentPDCD10, the gene mutated in cerebral cavernous malformation 3, is expressed in the neurovascular unit.
Tanriover G, Boylan AJ, Diluna ML, Pricola KL, Louvi A, Gunel M. PDCD10, the gene mutated in cerebral cavernous malformation 3, is expressed in the neurovascular unit. Neurosurgery 2008, 62: 930-8; discussion 938. PMID: 18496199, DOI: 10.1227/01.neu.0000318179.02912.ca.Peer-Reviewed Original ResearchConceptsMultiple organ systemsNeurovascular unitPostnatal mouse brainCerebral cavernous malformation 3Mouse brainCell death 10 geneArterial endotheliumOrgan systemsGranule cell layerMessenger ribonucleic acid expressionRibonucleic acid expressionCCM3/PDCD10Brainstem tissueEmbryonic mouse brainSeptal nucleusCortical plateDentate gyrusHypothalamic nucleiOlfactory bulbHuman cerebralInferior colliculusSolid organ tissuesVenous structuresVenous endotheliumDisease pathogenesisLinking Notch signaling to ischemic stroke
Arboleda-Velasquez JF, Zhou Z, Shin HK, Louvi A, Kim HH, Savitz SI, Liao JK, Salomone S, Ayata C, Moskowitz MA, Artavanis-Tsakonas S. Linking Notch signaling to ischemic stroke. Proceedings Of The National Academy Of Sciences Of The United States Of America 2008, 105: 4856-4861. PMID: 18347334, PMCID: PMC2290794, DOI: 10.1073/pnas.0709867105.Peer-Reviewed Original ResearchConceptsVascular smooth muscle cellsSmooth muscle cellsGenetic rescue experimentsUnderlying cellular pathwaysSpecific gene targetsKnockout mouse modelCellular pathwaysIschemic strokeGene targetsRescue experimentsSMC functionLong-term neurological disabilityMolecular analysisPathophysiology of strokeIschemic phenotypeMuscle cellsNotch-3Neurological disabilityCommon causeMouse modelStriking susceptibilityParaloguesStrokeNotchPhenotypeCyst formation and activation of the extracellular regulated kinase pathway after kidney specific inactivation of Pkd1
Shibazaki S, Yu Z, Nishio S, Tian X, Thomson RB, Mitobe M, Louvi A, Velazquez H, Ishibe S, Cantley LG, Igarashi P, Somlo S. Cyst formation and activation of the extracellular regulated kinase pathway after kidney specific inactivation of Pkd1. Human Molecular Genetics 2008, 17: 1505-1516. PMID: 18263604, PMCID: PMC2902289, DOI: 10.1093/hmg/ddn039.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisButadienesCell ProliferationCystsDisease Models, AnimalEnzyme ActivationKidneyMAP Kinase Kinase 1MAP Kinase Kinase 2MiceMice, Mutant StrainsMitogen-Activated Protein Kinase 1Mitogen-Activated Protein Kinase 3NitrilesPolycystic Kidney, Autosomal DominantProtein Kinase InhibitorsTRPP Cation ChannelsConceptsCyst formationERK1/2 activationPostnatal day 21Renal cystic diseaseWeeks of birthCyst cell proliferationPolycystic kidney diseaseKinase pathwayKidney tubule cellsKidney-specific inactivationRenal failureMEK1/2 inhibitor U0126Kidney diseaseCystic diseaseMAPK/ERKMAPK/ERK activationPresence of ciliaProliferative indexCyst growthCyst expansionDay 21Tubule cellsBrdU uptakeCystic kidneysBromodeoxyuridine incorporation
2007
The derivatives of the Wnt3a lineage in the central nervous system
Louvi A, Yoshida M, Grove EA. The derivatives of the Wnt3a lineage in the central nervous system. The Journal Of Comparative Neurology 2007, 504: 550-569. PMID: 17701978, DOI: 10.1002/cne.21461.Peer-Reviewed Original ResearchConceptsSpinal cordCervical spinal cordTrigeminal sensory systemRostral spinal cordCentral nervous systemCentral auditory systemDorsal midlineGenetic fate mappingSpecific functional networksAdult brainNervous systemDorsal halfBrain structuresCordLineage cellsAuditory systemMidbrainCell fate specificationVertebrate neural tubeNeural tubeFate mappingFunctional networksTransient gene expressionMidlineFate specification