2025
PTEN mutations impair CSF dynamics and cortical networks by dysregulating periventricular neural progenitors
DeSpenza T, Kiziltug E, Allington G, Barson D, McGee S, O’Connor D, Robert S, Mekbib K, Nanda P, Greenberg A, Singh A, Duy P, Mandino F, Zhao S, Lynn A, Reeves B, Marlier A, Getz S, Nelson-Williams C, Shimelis H, Walsh L, Zhang J, Wang W, Prina M, OuYang A, Abdulkareem A, Smith H, Shohfi J, Mehta N, Dennis E, Reduron L, Hong J, Butler W, Carter B, Deniz E, Lake E, Constable R, Sahin M, Srivastava S, Winden K, Hoffman E, Carlson M, Gunel M, Lifton R, Alper S, Jin S, Crair M, Moreno-De-Luca A, Luikart B, Kahle K. PTEN mutations impair CSF dynamics and cortical networks by dysregulating periventricular neural progenitors. Nature Neuroscience 2025, 28: 536-557. PMID: 39994410, DOI: 10.1038/s41593-024-01865-3.Peer-Reviewed Original ResearchConceptsNeural progenitor cellsCongenital hydrocephalusCSF dynamicsIncreased CSF productionDe novo mutationsFrequent monogenic causeEverolimus treatmentCSF shuntingNonsurgical treatmentPTEN mutationsAqueductal stenosisInhibitory interneuronsVentriculomegalyProgenitor cellsChoroid plexusMonogenic causeCortical networksIncreased survivalBrain ventriclesCortical deficitsNeural progenitorsGene PTENCSF productionNkx2.1PTEN
2024
Comparative single-cell multiome identifies evolutionary changes in neural progenitor cells during primate brain development
Liu Y, Luo X, Sun Y, Chen K, Hu T, You B, Xu J, Zhang F, Cheng Q, Meng X, Yan T, Li X, Qi X, He X, Guo X, Li C, Su B. Comparative single-cell multiome identifies evolutionary changes in neural progenitor cells during primate brain development. Developmental Cell 2024, 60: 414-428.e8. PMID: 39481377, DOI: 10.1016/j.devcel.2024.10.005.Peer-Reviewed Original ResearchEvolutionary changesDistal regulatory elementsGene regulatory mechanismsExtracellular matrixSingle-cell multiomicsProgenitor cellsTranscriptional divergenceEvolutionary divergenceChromatin regionsChromatin accessibilityNeural progenitorsRegulatory elementsSequence changesTranscriptional rewiringGenetic mechanismsMouse prefrontal cortexRegulatory mechanismsPrefrontal cortexHuman neural progenitorsHuman-specific featuresUpper-layer neuronsNeural progenitor cellsChromatinCellular propertiesProgenitor proliferationDysregulation of FLVCR1a-dependent mitochondrial calcium handling in neural progenitors causes congenital hydrocephalus
Bertino F, Mukherjee D, Bonora M, Bagowski C, Nardelli J, Metani L, Venturini D, Chianese D, Santander N, Salaroglio I, Hentschel A, Quarta E, Genova T, McKinney A, Allocco A, Fiorito V, Petrillo S, Ammirata G, De Giorgio F, Dennis E, Allington G, Maier F, Shoukier M, Gloning K, Munaron L, Mussano F, Salsano E, Pareyson D, di Rocco M, Altruda F, Panagiotakos G, Kahle K, Gressens P, Riganti C, Pinton P, Roos A, Arnold T, Tolosano E, Chiabrando D. Dysregulation of FLVCR1a-dependent mitochondrial calcium handling in neural progenitors causes congenital hydrocephalus. Cell Reports Medicine 2024, 5: 101647. PMID: 39019006, PMCID: PMC11293339, DOI: 10.1016/j.xcrm.2024.101647.Peer-Reviewed Original ResearchConceptsCongenital hydrocephalusCalcium handlingNeural progenitor cellsMitochondrial calcium handlingMouse neural progenitor cellsFLVCR1 geneMitochondrial calcium levelsVentricular dilatationLive birthsCalcium levelsProgenitor cellsClinical challengeVentricle enlargementPathogenetic mechanismsSevere formCortical neurogenesisNeural progenitorsFLVCR1aMitochondria-associated membranesHydrocephalusMiceFLVCR1CH genesMolecular mechanismsMetabolic activityLateral expansion of the mammalian cerebral cortex is related to anchorage of centrosomes in apical neural progenitors
Morozov Y, Rakic P. Lateral expansion of the mammalian cerebral cortex is related to anchorage of centrosomes in apical neural progenitors. Cerebral Cortex 2024, 34: bhae293. PMID: 39024157, PMCID: PMC11485267, DOI: 10.1093/cercor/bhae293.Peer-Reviewed Original ResearchConceptsNeural progenitor cellsProgenitor cellsVentricular zoneCerebral cortexBasolateral cell membraneApical anchorageProlonged neurogenesisMammalian cerebral cortexPrimary ciliaApical neural progenitorsCell membraneFraction of cellsNeural progenitorsStem cellsCerebral neurogenesisApical segmentsDevelopment of ciliaNuclear translocationMicrotubule organizing centerNeurogenesisCellsMacaque monkeysSpecies-specific differencesCortexBasal bodiesA novel method for culturing enteric neurons generates neurospheres containing functional myenteric neuronal subtypes
Mandal A, Moneme C, Tewari B, Goldstein A, Sontheimer H, Cheng L, Moore S, Levin D. A novel method for culturing enteric neurons generates neurospheres containing functional myenteric neuronal subtypes. Journal Of Neuroscience Methods 2024, 407: 110144. PMID: 38670535, PMCID: PMC11144385, DOI: 10.1016/j.jneumeth.2024.110144.Peer-Reviewed Original ResearchEnteric neuronsEnteric nervous systemPresence of sodium channel blockersProgenitor cellsProgenitor cell marker nestinAction potentialsNeural progenitor cell markers nestinNeural stemMyenteric plexus cellsActivate enteric neuronsCultured enteric neuronsCells expressing Sox2Differentiation culture systemSodium channel blockersMurine small intestineNeural progenitor cellsTubulin beta IIIDays of differentiationChannel blockersDifferentiated neurospheresNeuN immunofluorescenceEnteric neurospheresNeuronal subtypesMarker nestinPlexus cells
2023
Exploring therapeutic strategies for infantile neuronal axonal dystrophy (INAD/PARK14)
Lin G, Tepe B, McGrane G, Tipon R, Croft G, Panwala L, Hope A, Liang A, Zuo Z, Byeon S, Wang L, Pandey A, Bellen H. Exploring therapeutic strategies for infantile neuronal axonal dystrophy (INAD/PARK14). ELife 2023, 12: e82555. PMID: 36645408, PMCID: PMC9889087, DOI: 10.7554/elife.82555.Peer-Reviewed Original ResearchConceptsPatient-derived neural progenitor cellsNeural progenitor cellsPatient-derived neuronsPediatric neurodegenerative disorderRetromer functionMitochondrial morphologyEndolysosomal pathwayMitochondrial defectsProlong lifespanNeurodegenerative phenotypeProgenitor cellsMouse modelRecessive variantsNeurodegenerative disordersGene therapy approachesPathwayInfantile neuroaxonal dystrophyHomologCellsTherapeutic strategiesAzoramidePurkinje cellsFliesPhenotypeMetabolism
2022
Postmitotic accumulation of histone variant H3.3 in new cortical neurons establishes neuronal chromatin, transcriptome, and identity
Funk O, Qalieh Y, Doyle D, Lam M, Kwan K. Postmitotic accumulation of histone variant H3.3 in new cortical neurons establishes neuronal chromatin, transcriptome, and identity. Proceedings Of The National Academy Of Sciences Of The United States Of America 2022, 119: e2116956119. PMID: 35930666, PMCID: PMC9371731, DOI: 10.1073/pnas.2116956119.Peer-Reviewed Original ResearchConceptsNeuronal chromatinHistone variantsVariant H3.3Histone H3 variant H3.3Replication-coupled depositionHistone variant H3.3Replication-dependent histonesKey developmental roleNucleosome turnoverNeural progenitor cellsChromatin stateHistone replacementNeuronal transcriptomeModification landscapeDevelopmental phenotypesGene regulationTranscriptional disruptionH3.3Neuronal lifespanCellular phenotypesHistone H3 levelsNeuronal identityDevelopmental roleTranscriptomePostmitotic cells
2020
Symmetric neural progenitor divisions require chromatin-mediated homologous recombination DNA repair by Ino80
Keil J, Doyle D, Qalieh A, Lam M, Funk O, Qalieh Y, Shi L, Mohan N, Sorel A, Kwan K. Symmetric neural progenitor divisions require chromatin-mediated homologous recombination DNA repair by Ino80. Nature Communications 2020, 11: 3839. PMID: 32737294, PMCID: PMC7395731, DOI: 10.1038/s41467-020-17551-4.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisATPases Associated with Diverse Cellular ActivitiesBRCA2 ProteinCell DivisionChromatinChromatin Assembly and DisassemblyDNADNA Breaks, Double-StrandedDNA-Binding ProteinsEmbryo, MammalianGene Expression Regulation, DevelopmentalMiceMice, TransgenicNeocortexNeural Stem CellsNeurogenesisRecombinational DNA RepairSignal TransductionTumor Suppressor Protein p53YY1 Transcription FactorConceptsHomologous recombination DNA repairDNA repairIno80 deletionNeural progenitor cellsChromatin-mediated transcriptional regulationDNA double-strand break repairDouble-strand break repairSpatiotemporal gene expressionLoss of INO80HR DNA repairUnrepaired DNA breaksAsymmetric neurogenic divisionsNeural progenitor divisionsDNA damage repairP53-dependent apoptosisINO80 functionGenome maintenanceTranscriptional regulationINO80Break repairDNA breaksProgenitor divisionsDamage repairGene expressionNPC divisionTranscriptional signatures of participant-derived neural progenitor cells and neurons implicate altered Wnt signaling in Phelan-McDermid syndrome and autism
Breen MS, Browne A, Hoffman GE, Stathopoulos S, Brennand K, Buxbaum JD, Drapeau E. Transcriptional signatures of participant-derived neural progenitor cells and neurons implicate altered Wnt signaling in Phelan-McDermid syndrome and autism. Molecular Autism 2020, 11: 53. PMID: 32560742, PMCID: PMC7304190, DOI: 10.1186/s13229-020-00355-0.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAutistic DisorderChildChild, PreschoolChromosome DeletionChromosome DisordersChromosomes, Human, Pair 22FemaleGene Expression ProfilingGene Expression RegulationHumansInduced Pluripotent Stem CellsMaleNeural Stem CellsNeuronsReproducibility of ResultsWnt Signaling PathwayConceptsNeural progenitor cellsTranscriptional signatureGene co-expression network analysisHiPSC-NPCsCo-expression network analysisIndependent biological samplesHiPSC-derived neural cellsProgenitor cellsPostsynaptic density genesDistinct transcriptional signaturesGenetic risk lociHuman-induced pluripotent stem cellsPluripotent stem cellsPotassium channel activityProtein translationSpecific neurobiological pathwaysTranscriptional differencesEmbryonic developmentLoss of SHANK3Risk lociHiPSC neuronsMorphological phenotypesWnt pathwayGenesHiPSC clonesTranscriptional Signatures of Participant-Derived Neural Progenitor Cells and Neurons Implicate Altered WNT Signaling in Phelan-McDermid Syndrome and Autism
Breen M, Browne A, Hoffman G, Stathopoulous S, Brennand K, Buxbaum J, Drapeau E. Transcriptional Signatures of Participant-Derived Neural Progenitor Cells and Neurons Implicate Altered WNT Signaling in Phelan-McDermid Syndrome and Autism. Biological Psychiatry 2020, 87: s456-s457. DOI: 10.1016/j.biopsych.2020.02.1162.Peer-Reviewed Original ResearchNeural progenitor cellsPhelan-McDermid syndromeProgenitor cellsTranscriptional signatureAltered WntSyndromeNeuronsASCL1- and DLX2-induced GABAergic neurons from hiPSC-derived NPCs
Barretto N, Zhang H, Powell SK, Fernando MB, Zhang S, Flaherty EK, Ho SM, Slesinger PA, Duan J, Brennand KJ. ASCL1- and DLX2-induced GABAergic neurons from hiPSC-derived NPCs. Journal Of Neuroscience Methods 2020, 334: 108548. PMID: 32065989, PMCID: PMC7426253, DOI: 10.1016/j.jneumeth.2019.108548.Peer-Reviewed Original ResearchNeural progenitor cellsHiPSC-NPCsSomatic cell reprogrammingGABAergic neuronsHiPSC-derived neural progenitor cellsDifferentiation of hiPSCsDistinct transcriptional profilesPluripotent stem cellsCell reprogrammingPatient-derived cellsElectrophysiological maturityFunctional GABAergic neuronsTranscriptional profilesNeuronal inductionStem cellsProgenitor cellsLentiviral overexpressionPure populationsDlx2Study of diseasesAscl1HiPSCsNeuronal populationsInduction protocolCell source
2019
Congenital human cytomegalovirus infection and neurologic diseases in newborns
Zhang XY, Fang F. Congenital human cytomegalovirus infection and neurologic diseases in newborns. Chinese Medical Journal 2019, 132: 2109-2118. PMID: 31433331, PMCID: PMC6793797, DOI: 10.1097/cm9.0000000000000404.Peer-Reviewed Original ResearchConceptsNeurologic diseaseCCMV infectionNeurologic damageCentral nervous system infectionCongenital human cytomegalovirus (HCMV) infectionNervous system infectionNervous system diseasesHuman cytomegalovirus infectionClinical treatment methodsCMV gene productsNeural progenitor cellsWeb of SciencePlacental inflammationNeuroimmune responseCytomegalovirus infectionOphthalmic complicationsSystem infectionCerebral neoplasmsNeurologic abnormalitiesNeonatal malformationsEarly gestationNeurodevelopmental abnormalitiesSystem diseasesDifferent diagnosesHearing impairmentThe Psychiatric Risk Gene NT5C2 Regulates Adenosine Monophosphate-Activated Protein Kinase Signaling and Protein Translation in Human Neural Progenitor Cells
Duarte RRR, Bachtel ND, Côtel MC, Lee SH, Selvackadunco S, Watson IA, Hovsepian GA, Troakes C, Breen GD, Nixon DF, Murray RM, Bray NJ, Eleftherianos I, Vernon AC, Powell TR, Srivastava DP. The Psychiatric Risk Gene NT5C2 Regulates Adenosine Monophosphate-Activated Protein Kinase Signaling and Protein Translation in Human Neural Progenitor Cells. Biological Psychiatry 2019, 86: 120-130. PMID: 31097295, PMCID: PMC6614717, DOI: 10.1016/j.biopsych.2019.03.977.Peer-Reviewed Original ResearchConceptsHuman neural progenitor cellsProtein translationNeural progenitor cellsMotility behaviorAvailable expression dataRibosomal protein S6Protein Kinase SignalingRegulation of AMPKProgenitor cellsNutrient sensing mechanismsProtein kinase alphaQuantitative polymerase chain reactionPsychiatric risk allelesDrosophila melanogasterTranscriptional changesKinase signalingProtein S6Transcriptomic profilingRNA interferenceNeural stem cellsExpression changesKinase alphaUnknown roleExpression dataHuman dorsolateral prefrontal cortex22THE PSYCHIATRIC RISK GENE NT5C2 REGULATES PROTEIN TRANSLATION IN HUMAN NEURAL PROGENITOR CELLS, AND IS INVOLVED IN LOCOMOTOR BEHAVIOUR IN DROSOPHILA MELANOGASTER
Duarte R, Bachtel N, Eleftherianos I, Nixon D, Murray R, Bray N, Powell T, Srivastava D. 22THE PSYCHIATRIC RISK GENE NT5C2 REGULATES PROTEIN TRANSLATION IN HUMAN NEURAL PROGENITOR CELLS, AND IS INVOLVED IN LOCOMOTOR BEHAVIOUR IN DROSOPHILA MELANOGASTER. European Neuropsychopharmacology 2019, 29: s1078. DOI: 10.1016/j.euroneuro.2018.08.029.Peer-Reviewed Original Research
2018
Neuron-specific signatures in the chromosomal connectome associated with schizophrenia risk
Rajarajan P, Borrman T, Liao W, Schrode N, Flaherty E, Casiño C, Powell S, Yashaswini C, LaMarca EA, Kassim B, Javidfar B, Espeso-Gil S, Li A, Won H, Geschwind DH, Ho SM, MacDonald M, Hoffman GE, Roussos P, Zhang B, Hahn CG, Weng Z, Brennand KJ, Akbarian S. Neuron-specific signatures in the chromosomal connectome associated with schizophrenia risk. Science 2018, 362 PMID: 30545851, PMCID: PMC6408958, DOI: 10.1126/science.aat4311.Peer-Reviewed Original ResearchMeSH KeywordsBrainCells, CulturedChromatinChromatin Assembly and DisassemblyChromosomes, HumanConnectomeEpigenesis, GeneticGene Expression Regulation, DevelopmentalGenetic Predisposition to DiseaseGenome-Wide Association StudyGenome, HumanHumansMaleNeural Stem CellsNeurogenesisNeurogliaNeuronsNucleic Acid ConformationProtein Interaction MapsProteomicsRiskSchizophreniaTranscription, GeneticTranscriptomeConceptsCoordinated transcriptional regulationThree-dimensional genomeSpatial genome organizationChromosomal contact mapsNeural progenitor cellsSchizophrenia risk variantsGenome organizationChromatin remodelingChromosomal conformationTranscriptional regulationProteomic interactionsDevelopmental remodelingHeritable riskGlial differentiationRisk variantsContact mapsProgenitor cellsVariant sequencesGenesConformation changeNeuronal connectivitySchizophrenia riskSequenceNeuropsychiatric diseasesDistal targetsExpression-based drug screening of neural progenitor cells from individuals with schizophrenia
Readhead B, Hartley BJ, Eastwood BJ, Collier DA, Evans D, Farias R, He C, Hoffman G, Sklar P, Dudley JT, Schadt EE, Savić R, Brennand KJ. Expression-based drug screening of neural progenitor cells from individuals with schizophrenia. Nature Communications 2018, 9: 4412. PMID: 30356048, PMCID: PMC6200740, DOI: 10.1038/s41467-018-06515-4.Peer-Reviewed Original ResearchConceptsNeural progenitor cellsHiPSC neural progenitor cellsCell typesCancer cell linesGene expression differencesProgenitor cellsDisease-associated genesPatient-specific platformPluripotent stem cellsTranscriptional responseExpression differencesTranscriptional signatureTranscriptomic signaturesStem cellsCell linesDependent mannerDrug discoveryDrug screeningCellsNeuropsychiatric disordersSchizophreniaBest treatmentDrugsDiscoveryGenesAspm knockout ferret reveals an evolutionary mechanism governing cerebral cortical size
Johnson MB, Sun X, Kodani A, Borges-Monroy R, Girskis KM, Ryu SC, Wang PP, Patel K, Gonzalez DM, Woo YM, Yan Z, Liang B, Smith RS, Chatterjee M, Coman D, Papademetris X, Staib LH, Hyder F, Mandeville JB, Grant PE, Im K, Kwak H, Engelhardt JF, Walsh CA, Bae BI. Aspm knockout ferret reveals an evolutionary mechanism governing cerebral cortical size. Nature 2018, 556: 370-375. PMID: 29643508, PMCID: PMC6095461, DOI: 10.1038/s41586-018-0035-0.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsBiological EvolutionCalmodulin-Binding ProteinsCentrosomeCerebral CortexDisease Models, AnimalFemaleFerretsGene DeletionGene EditingGene Expression Regulation, DevelopmentalGene Knockout TechniquesGerm-Line MutationHumansMaleMiceMicrocephalyNerve Tissue ProteinsNeural Stem CellsOrgan SizeTranscription, GeneticConceptsVentricular radial glial cellsEvolutionary mechanismsRadial glial cellsOuter radial gliaHuman primary microcephalyProtein sequence homologyAbnormal spindle-like microcephalyCerebral cortical sizeGlial cellsCortical sizeUndifferentiated cell typesNeural progenitor cellsRadial gliaASPM proteinCerebral cortical expansionMicrocephaly genesDivergent functionsGenome editingSequence homologyDifferentiated progenitorsOuter subventricular zoneCortical expansionPrimary microcephalyCell typesGermline knockoutBlocking Zika virus vertical transmission
Mesci P, Macia A, Moore SM, Shiryaev SA, Pinto A, Huang CT, Tejwani L, Fernandes IR, Suarez NA, Kolar MJ, Montefusco S, Rosenberg SC, Herai RH, Cugola FR, Russo FB, Sheets N, Saghatelian A, Shresta S, Momper JD, Siqueira-Neto JL, Corbett KD, Beltrão-Braga PCB, Terskikh AV, Muotri AR. Blocking Zika virus vertical transmission. Scientific Reports 2018, 8: 1218. PMID: 29352135, PMCID: PMC5775359, DOI: 10.1038/s41598-018-19526-4.Peer-Reviewed Original ResearchNeural progenitor cellsZika virusViral burdenVertical transmissionSOF treatmentZika virus vertical transmissionAnti-ZIKV activityAntiviral immune responseImmunodeficient mouse modelHuman neural cell typesHuman neural progenitor cellsCell deathNucleotide analog inhibitorBody of evidenceChronic infectionNeural cell typesImmune responseMouse modelCongenital malformationsAnimal modelsVaccine developmentInfected individualsSofosbuvirProgenitor cellsTreatment
2017
Transcriptional signatures of schizophrenia in hiPSC-derived NPCs and neurons are concordant with post-mortem adult brains
Hoffman GE, Hartley BJ, Flaherty E, Ladran I, Gochman P, Ruderfer DM, Stahl EA, Rapoport J, Sklar P, Brennand KJ. Transcriptional signatures of schizophrenia in hiPSC-derived NPCs and neurons are concordant with post-mortem adult brains. Nature Communications 2017, 8: 2225. PMID: 29263384, PMCID: PMC5738408, DOI: 10.1038/s41467-017-02330-5.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAntigens, SurfaceAutopsyBrainCase-Control StudiesChildDNA Copy Number VariationsFemaleHumansInduced Pluripotent Stem CellsLinear ModelsMaleNanog Homeobox ProteinNestinNeural Stem CellsNeuronsOctamer Transcription Factor-3ProteoglycansRNA, MessengerSchizophreniaSequence Analysis, RNASOXB1 Transcription FactorsStage-Specific Embryonic AntigensSynapsinsTranscriptomeYoung AdultCerebral organoids reveal early cortical maldevelopment in schizophrenia—computational anatomy and genomics, role of FGFR1
Stachowiak E, Benson C, Narla S, Dimitri A, Chuye L, Dhiman S, Harikrishnan K, Elahi S, Freedman D, Brennand K, Sarder P, Stachowiak M. Cerebral organoids reveal early cortical maldevelopment in schizophrenia—computational anatomy and genomics, role of FGFR1. Translational Psychiatry 2017, 7: 6. PMID: 30446636, PMCID: PMC5802550, DOI: 10.1038/s41398-017-0054-x.Peer-Reviewed Original ResearchConceptsNeural progenitor cellsCerebral organoidsSchizophrenia patientsVentricular zoneInduced pluripotent stem cellsCortical neuronal maturationUtero brain developmentRole of FGFR1Stem cellsIntracortical connectivityFirst trimesterCortical maldevelopmentCortical malformationsPreventive treatmentCalretinin interneuronsNeuronal maturationSubcortical regionsControl individualsPioneer neuronsCortical zoneBrain developmentHuman embryonic stem cellsProgenitor cellsIntegrative nuclear FGFR1FGFR1 gene
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