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 productionNkx2.1PTENResolving the three-dimensional interactome of human accelerated regions during human and chimpanzee neurodevelopment
Pal A, Noble M, Morales M, Pal R, Baumgartner M, Yang J, Yim K, Uebbing S, Noonan J. Resolving the three-dimensional interactome of human accelerated regions during human and chimpanzee neurodevelopment. Cell 2025, 188: 1504-1523.e27. PMID: 39889695, PMCID: PMC11928272, DOI: 10.1016/j.cell.2025.01.007.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBrainGene Expression Regulation, DevelopmentalHumansNeural Stem CellsNeurogenesisPan troglodytesSpecies SpecificitySignificance of birth in the maintenance of quiescent neural stem cells
Kawase K, Nakamura Y, Wolbeck L, Takemura S, Zaitsu K, Ando T, Jinnou H, Sawada M, Nakajima C, Rydbirk R, Gokenya S, Ito A, Fujiyama H, Saito A, Iguchi A, Kratimenos P, Ishibashi N, Gallo V, Iwata O, Saitoh S, Khodosevich K, Sawamoto K. Significance of birth in the maintenance of quiescent neural stem cells. Science Advances 2025, 11: eadn6377. PMID: 39841848, PMCID: PMC11753423, DOI: 10.1126/sciadv.adn6377.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnimals, NewbornBrainCell ProliferationEpendymoglial CellsFemaleGlutamineMiceNeural Stem CellsNeurogenesisParturitionConceptsNeural stem cellsQuiescent neural stem cellsStem cellsRadial gliaNeural stem cell poolAcquisition of quiescenceEmbryonic neural stem cellsPreterm birthPostnatal neural stem cellsCellular processesPostnatal neurogenesisGlutamine metabolismPostnatal brainLong-term maintenanceDevelopmental processesBirthNeurogenesisPretermCells
2024
Cell-specific cross-talk proteomics reveals cathepsin B signaling as a driver of glioblastoma malignancy near the subventricular zone
Norton E, Whaley L, Jones V, Brooks M, Russo M, Morderer D, Jessen E, Schiapparelli P, Ramos-Fresnedo A, Zarco N, Carrano A, Rossoll W, Asmann Y, Lam T, Chaichana K, Anastasiadis P, Quiñones-Hinojosa A, Guerrero-Cázares H. Cell-specific cross-talk proteomics reveals cathepsin B signaling as a driver of glioblastoma malignancy near the subventricular zone. Science Advances 2024, 10: eadn1607. PMID: 39110807, PMCID: PMC11305394, DOI: 10.1126/sciadv.adn1607.Peer-Reviewed Original ResearchConceptsBrain tumor-initiating cellsLateral ventricleNeuronal maturationMalignancy-associated phenotypesSubventricular zone contactIncreased expression of cathepsin BMalignant primary brain tumorTumor-initiating cellsAggressive malignant primary brain tumorPrimary brain tumorTumor microenvironment researchExpression of cathepsin BNeural stem/progenitor cellsCathepsin BInduction of senescenceStem/progenitor cellsCell-intrinsicSubventricular zoneCross-talkTherapeutic strategiesBrain tumorsIncreased expressionGBM biologyLentiviral knockdownGlioblastomaDysregulation 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 bodies
2023
Molecular programs of regional specification and neural stem cell fate progression in macaque telencephalon
Micali N, Ma S, Li M, Kim S, Mato-Blanco X, Sindhu S, Arellano J, Gao T, Shibata M, Gobeske K, Duque A, Santpere G, Sestan N, Rakic P. Molecular programs of regional specification and neural stem cell fate progression in macaque telencephalon. Science 2023, 382: eadf3786. PMID: 37824652, PMCID: PMC10705812, DOI: 10.1126/science.adf3786.Peer-Reviewed Original ResearchMicroglia Maintain Homeostatic Conditions in the Developing Rostral Migratory Stream
Meller S, Hernandez L, Martin-Lopez E, Kloos Z, Liberia T, Greer C. Microglia Maintain Homeostatic Conditions in the Developing Rostral Migratory Stream. ENeuro 2023, 10: eneuro.0197-22.2023. PMID: 36697258, PMCID: PMC9910579, DOI: 10.1523/eneuro.0197-22.2023.Peer-Reviewed Original Research
2022
A neural stem cell paradigm of pediatric hydrocephalus
Duy PQ, Rakic P, Alper SL, Robert SM, Kundishora AJ, Butler WE, Walsh CA, Sestan N, Geschwind DH, Jin SC, Kahle KT. A neural stem cell paradigm of pediatric hydrocephalus. Cerebral Cortex 2022, 33: 4262-4279. PMID: 36097331, PMCID: PMC10110448, DOI: 10.1093/cercor/bhac341.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBrainCerebral VentriclesChildHumansHydrocephalusNeural Stem CellsNeurosurgical ProceduresConceptsPediatric hydrocephalusPrimary treatment strategyOptimal surgical managementDevelopmental brain malformationsAnimal model studiesSurgical managementCerebral ventricleCSF diversionVentricular distentionHydrocephalic childrenTreatment strategiesBrain malformationsNeurodevelopmental disabilitiesGerminal neuroepitheliumHydrocephalusStem cell paradigmNeural stem cell fateRecent human geneticBrain surgeryCSF circulationBrain ventriclesCSF volumeNeuroprogenitor cellsBrain defectsCSF homeostasisBrain ventricles as windows into brain development and disease
Duy PQ, Rakic P, Alper SL, Butler WE, Walsh CA, Sestan N, Geschwind DH, Jin SC, Kahle KT. Brain ventricles as windows into brain development and disease. Neuron 2022, 110: 12-15. PMID: 34990576, PMCID: PMC9212067, DOI: 10.1016/j.neuron.2021.12.009.Peer-Reviewed Original ResearchNeural Stem Cells in Adult Mammals are not Astrocytes
Velloso F, Shankar S, Parpura V, Rakic P, Levison S. Neural Stem Cells in Adult Mammals are not Astrocytes. ASN Neuro 2022, 14: 17590914221134739. PMID: 36330653, PMCID: PMC9638700, DOI: 10.1177/17590914221134739.Peer-Reviewed Original ResearchConceptsAdult mammalian subventricular zoneNeural stem cellsMammalian subventricular zoneMammalian neural stem cellsComparative transcriptomic analysisDistinct gene expression profilesStem cellsAdult mammalian neural stem cellsGene expression profilesSingle-cell RNAseqFunction of NSCsMurine neural stem cellsSubventricular zoneTranscriptomic analysisExpression profilesAdult murine neural stem cellsCell sortingAdult mammalsFunction of astrocytesCellsNew neuronsSubtypes of astrocytesMammalsRNAseqNiche
2021
Endothelial cell secreted VEGF-C enhances NSC VEGFR3 expression and promotes NSC survival
Matta R, Feng Y, Sansing LH, Gonzalez AL. Endothelial cell secreted VEGF-C enhances NSC VEGFR3 expression and promotes NSC survival. Stem Cell Research 2021, 53: 102318. PMID: 33836422, PMCID: PMC8243729, DOI: 10.1016/j.scr.2021.102318.Peer-Reviewed Original ResearchLandmarks of human embryonic development inscribed in somatic mutations
Bizzotto S, Dou Y, Ganz J, Doan R, Kwon M, Bohrson C, Kim S, Bae T, Abyzov A, Network† N, Park P, Walsh C. Landmarks of human embryonic development inscribed in somatic mutations. Science 2021, 371: 1249-1253. PMID: 33737485, PMCID: PMC8170505, DOI: 10.1126/science.abe1544.Peer-Reviewed Original ResearchConceptsSomatic single nucleotide variantsHuman embryonic developmentEmbryonic developmentEarly embryonic cell divisionsTransposase-accessible chromatin sequencingSingle cellsSingle-nucleus assayHigh-depth whole-genome sequencingSingle-nucleus RNA sequencingEmbryonic cell divisionCell lineage informationDistinct germ layersOnset of gastrulationSingle nucleotide variantsOrganismal developmentWhole-genome sequencingExtraembryonic tissuesCell divisionRNA sequencingProgenitor poolLineage informationGerm layersEarly progenitorsMultiple tissuesSequencingEarly developmental asymmetries in cell lineage trees in living individuals
Fasching L, Jang Y, Tomasi S, Schreiner J, Tomasini L, Brady MV, Bae T, Sarangi V, Vasmatzis N, Wang Y, Szekely A, Fernandez TV, Leckman JF, Abyzov A, Vaccarino FM. Early developmental asymmetries in cell lineage trees in living individuals. Science 2021, 371: 1245-1248. PMID: 33737484, PMCID: PMC8324008, DOI: 10.1126/science.abe0981.Peer-Reviewed Original Research
2020
Massively parallel discovery of human-specific substitutions that alter enhancer activity
Uebbing S, Gockley J, Reilly SK, Kocher AA, Geller E, Gandotra N, Scharfe C, Cotney J, Noonan JP. Massively parallel discovery of human-specific substitutions that alter enhancer activity. Proceedings Of The National Academy Of Sciences Of The United States Of America 2020, 118: e2007049118. PMID: 33372131, PMCID: PMC7812811, DOI: 10.1073/pnas.2007049118.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBiological EvolutionEnhancer Elements, GeneticGenome, HumanHumansNeocortexNeural Stem CellsPan troglodytesTranscription FactorsConceptsHuman-specific substitutionsHuman-gained enhancersGenetic changesEnhancer functionEnhancer activityHuman-specific genetic changesHuman evolutionGene regulatory elementsBackground genetic variationAncestral functionRegulatory evolutionEnhancer assaysGenetic variationRegulatory elementsNeural stem cellsHuman traitsNovel activityNonadditive wayRegulatory activityStem cellsFunctional impactDifferential activityParallel discoveryEnhancerEvolutionChemical mutagenesis of a GPCR ligand: Detoxifying “inflammo-attraction” to direct therapeutic stem cell migration
Lee J, Zhang R, Yan M, Duggineni S, Wakeman D, Niles W, Feng Y, Chen J, Hamblin M, Han E, Gonzalez R, Fang X, Zhu Y, Wang J, Xu Y, Wenger D, Seyfried T, An J, Sidman R, Huang Z, Snyder E. Chemical mutagenesis of a GPCR ligand: Detoxifying “inflammo-attraction” to direct therapeutic stem cell migration. Proceedings Of The National Academy Of Sciences Of The United States Of America 2020, 117: 31177-31188. PMID: 33219123, PMCID: PMC7733796, DOI: 10.1073/pnas.1911444117.Peer-Reviewed Original ResearchConceptsNeural stem cellsCXCR4 agonistPrototypical neurodegenerative diseaseDonor-derived cellsStem cellsCerebral cortexCNS injuryInflammatory chemokinesHost inflammationUndesirable inflammationCXCL-12Mouse modelTherapeutic impactChemokine CXCL12Stem cell propertiesCell engagementNeurodegenerative diseasesStem cell migrationNSC migrationAgonistsSynthetic functionInflammationChemokinesFundamental stem cell propertiesCXCL12Cannabinoid Type 1 Receptor is Undetectable in Rodent and Primate Cerebral Neural Stem Cells but Participates in Radial Neuronal Migration
Morozov YM, Mackie K, Rakic P. Cannabinoid Type 1 Receptor is Undetectable in Rodent and Primate Cerebral Neural Stem Cells but Participates in Radial Neuronal Migration. International Journal Of Molecular Sciences 2020, 21: 8657. PMID: 33212822, PMCID: PMC7696736, DOI: 10.3390/ijms21228657.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell MovementCell ProliferationMacaca mulattaMiceMice, KnockoutNeural Stem CellsNeurogenesisNeuronsReceptor, Cannabinoid, CB1ConceptsNeural stem cellsStem cellsCannabinoid type 1 receptorType 1 receptorFate determinationRadial neuronal migrationCell movementEmbryonic developmentIntracellular vesiclesCellular locationMRNA sequencingMolecular mechanismsCortical plateElectron microscopic reconstructionCellular proliferationNeuronal migrationZone cellsSubventricular zone cellsEmbryonic miceMolecular substratesSVZ cellsMicroscopic reconstructionRecreational cannabis useMacaque cerebral cortexPrimate neuronsExome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus
Jin SC, Dong W, Kundishora AJ, Panchagnula S, Moreno-De-Luca A, Furey CG, Allocco AA, Walker RL, Nelson-Williams C, Smith H, Dunbar A, Conine S, Lu Q, Zeng X, Sierant MC, Knight JR, Sullivan W, Duy PQ, DeSpenza T, Reeves BC, Karimy JK, Marlier A, Castaldi C, Tikhonova IR, Li B, Peña HP, Broach JR, Kabachelor EM, Ssenyonga P, Hehnly C, Ge L, Keren B, Timberlake AT, Goto J, Mangano FT, Johnston JM, Butler WE, Warf BC, Smith ER, Schiff SJ, Limbrick DD, Heuer G, Jackson EM, Iskandar BJ, Mane S, Haider S, Guclu B, Bayri Y, Sahin Y, Duncan CC, Apuzzo MLJ, DiLuna ML, Hoffman EJ, Sestan N, Ment LR, Alper SL, Bilguvar K, Geschwind DH, Günel M, Lifton RP, Kahle KT. Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus. Nature Medicine 2020, 26: 1754-1765. PMID: 33077954, PMCID: PMC7871900, DOI: 10.1038/s41591-020-1090-2.Peer-Reviewed Original ResearchConceptsCongenital hydrocephalusPoor neurodevelopmental outcomesPost-surgical patientsCerebrospinal fluid accumulationNeural stem cell biologyGenetic disruptionWhole-exome sequencingPrimary pathomechanismEarly brain developmentNeurodevelopmental outcomesHigh morbidityCSF diversionMutation burdenFluid accumulationBrain ventriclesCH casesBrain developmentDe novo mutationsPatientsExome sequencingCSF dynamicsDisease mechanismsHydrocephalusNovo mutationsCell typesDisease‐specific phenotypes in iPSC‐derived neural stem cells with POLG mutations
Liang K, Kristiansen C, Mostafavi S, Vatne G, Zantingh G, Kianian A, Tzoulis C, Høyland L, Ziegler M, Perez R, Furriol J, Zhang Z, Balafkan N, Hong Y, Siller R, Sullivan G, Bindoff L. Disease‐specific phenotypes in iPSC‐derived neural stem cells with POLG mutations. EMBO Molecular Medicine 2020, 12: emmm202012146. PMID: 32840960, PMCID: PMC7539330, DOI: 10.15252/emmm.202012146.Peer-Reviewed Original ResearchMeSH KeywordsDNA Polymerase gammaDNA, MitochondrialHumansInduced Pluripotent Stem CellsMutationNeural Stem CellsPhenotypeConceptsPOLG mutationsComplex ILoss of complex IHeterozygous POLG mutationsMitochondrial dysfunctionLoss of mtDNAFate determination processesHuman stem cell modelsNeural stem cellsMtDNA replicationIncreased UCP2 expressionStem cellsAssociated with POLG mutationsMtDNANAD+ metabolismActivating mitophagyPOLGNeurological phenotypePost-mortem brain tissueDisease-specific phenotypesPatient cellsStem cell modelMutationsBiochemical defectROS overproductionSymmetric 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 division
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