2024
CpG island turnover events predict evolutionary changes in enhancer activity
Kocher A, Dutrow E, Uebbing S, Yim K, Rosales Larios M, Baumgartner M, Nottoli T, Noonan J. CpG island turnover events predict evolutionary changes in enhancer activity. Genome Biology 2024, 25: 156. PMID: 38872220, PMCID: PMC11170920, DOI: 10.1186/s13059-024-03300-z.Peer-Reviewed Original ResearchConceptsHuman-gained enhancersCpG islandsFunction of transcriptional enhancersEvolution of biological diversityHuman CpG islandsGene regulatory changesInfluence enhancer activityCpG island contentHistone modification levelsEnhanced activitySpecies-specific activityTrait evolutionNucleotide substitutionsHistone modificationsTranscriptional enhancersMouse orthologEvolutionary changesTurnover eventsModification levelsMammalian speciesMultiple tissuesEmbryonic developmentMouse diencephalonHuman embryonic developmentSpecies
2023
Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations
Zhao S, Mekbib K, van der Ent M, Allington G, Prendergast A, Chau J, Smith H, Shohfi J, Ocken J, Duran D, Furey C, Hao L, Duy P, Reeves B, Zhang J, Nelson-Williams C, Chen D, Li B, Nottoli T, Bai S, Rolle M, Zeng X, Dong W, Fu P, Wang Y, Mane S, Piwowarczyk P, Fehnel K, See A, Iskandar B, Aagaard-Kienitz B, Moyer Q, Dennis E, Kiziltug E, Kundishora A, DeSpenza T, Greenberg A, Kidanemariam S, Hale A, Johnston J, Jackson E, Storm P, Lang S, Butler W, Carter B, Chapman P, Stapleton C, Patel A, Rodesch G, Smajda S, Berenstein A, Barak T, Erson-Omay E, Zhao H, Moreno-De-Luca A, Proctor M, Smith E, Orbach D, Alper S, Nicoli S, Boggon T, Lifton R, Gunel M, King P, Jin S, Kahle K. Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations. Nature Communications 2023, 14: 7452. PMID: 37978175, PMCID: PMC10656524, DOI: 10.1038/s41467-023-43062-z.Peer-Reviewed Original ResearchConceptsEphrin receptor B4Galen malformationBrain arteriovenous malformationsP120 RasGAPTransmitted variantsArteriovenous malformationsDe novo variantsSingle-cell transcriptomesSignificant burdenCerebrovascular developmentIntegrative genomic analysisEndothelial cellsVenous networkAdditional probandsMalformationsNovo variantsMissense variantsGenomic analysisDevelopmental angiogenesisVascular developmentDamaging variantsVeinRasGAPIntegrated analysisPatientsIsradipine therapy in Cacna1dIle772Met/+ mice ameliorates primary aldosteronism and neurologic abnormalities
Stölting G, Dinh H, Volkert M, Hellmig N, Schewe J, Hennicke L, Seidel E, Oberacher H, Zhang J, Lifton R, Urban I, Long M, Rivalan M, Nottoli T, Scholl U. Isradipine therapy in Cacna1dIle772Met/+ mice ameliorates primary aldosteronism and neurologic abnormalities. JCI Insight 2023, 8: e162468. PMID: 37698934, PMCID: PMC10619505, DOI: 10.1172/jci.insight.162468.Peer-Reviewed Original ResearchConceptsPrimary aldosteronismNeurologic abnormalitiesZona glomerulosaIntracellular calciumElevated aldosterone/renin ratioCalcium channel blocker isradipineAldosterone/renin ratioL-type calcium channel Cav1.3Aldosterone-producing lesionsAdrenal aldosterone-producing adenomaHigh-salt dietTonic-clonic seizuresChannel blocker isradipineReduced body weightAldosterone-producing adenomaTherapy of patientsElevated intracellular calciumFunction mutationsDe novo germline mutationsDays of ageIsradipine therapyAldosterone levelsRenin ratioSerum aldosteroneRotarod test
2022
Modeling uniquely human gene regulatory function via targeted humanization of the mouse genome
Dutrow EV, Emera D, Yim K, Uebbing S, Kocher AA, Krenzer M, Nottoli T, Burkhardt DB, Krishnaswamy S, Louvi A, Noonan JP. Modeling uniquely human gene regulatory function via targeted humanization of the mouse genome. Nature Communications 2022, 13: 304. PMID: 35027568, PMCID: PMC8758698, DOI: 10.1038/s41467-021-27899-w.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBase SequenceCell DifferentiationChondrocytesChondrogenesisEmbryo, MammalianEnhancer Elements, GeneticEpigenesis, GeneticExtremitiesGene Expression ProfilingGene Expression RegulationGene Knock-In TechniquesGenomeHomeodomain ProteinsHomozygoteHumansMesodermMice, Inbred C57BLModels, GeneticPan troglodytesPromoter Regions, GeneticTime FactorsConceptsHuman Accelerated RegionsGene expressionHuman-specific sequence changesDevelopmental gene regulationSingle-cell RNA sequencingGene regulatory functionsHuman evolutionEndogenous gene expressionAlters gene expressionSkeletal patterningMolecular functionsGene regulationChondrogenic mesenchymeMouse genomeRegulatory modificationHomozygous embryosLimb developmentTranscriptional enhancersTranscription factorsRNA sequencingEnhancer activityMouse embryosRegulatory functionsAccelerated regionSequence changes
2021
Mouse Embryonic Fibroblasts Isolated From Nthl1 D227Y Knockin Mice Exhibit Defective DNA Repair and Increased Genome Instability
Marsden CG, Das L, Nottoli TP, Kathe SD, Doublié S, Wallace SS, Sweasy JB. Mouse Embryonic Fibroblasts Isolated From Nthl1 D227Y Knockin Mice Exhibit Defective DNA Repair and Increased Genome Instability. DNA Repair 2021, 109: 103247. PMID: 34826736, PMCID: PMC8787541, DOI: 10.1016/j.dnarep.2021.103247.Peer-Reviewed Original ResearchConceptsGenomic instabilityEmbryonic fibroblastsExogenous DNA damaging agentsBifunctional DNA glycosylaseIncreased genome instabilityGenome editing technologyMurine embryonic fibroblastsDNA damaging agentsMouse embryonic fibroblastsNormal cellular metabolismDefective DNA repairHomozygous stateDNA glycosylase 1Genome instabilityMutant MEFsReplication stressDNA repairCellular phenotypesDNA glycosylaseEditing technologyCellular metabolismDamaging agentsWT proteinOxidative DNA damagePyrimidine lesionsEnhanced Ca2+ signaling, mild primary aldosteronism, and hypertension in a familial hyperaldosteronism mouse model (Cacna1hM1560V/+)
Seidel E, Schewe J, Zhang J, Dinh HA, Forslund SK, Markó L, Hellmig N, Peters J, Muller DN, Lifton RP, Nottoli T, Stölting G, Scholl UI. Enhanced Ca2+ signaling, mild primary aldosteronism, and hypertension in a familial hyperaldosteronism mouse model (Cacna1hM1560V/+). Proceedings Of The National Academy Of Sciences Of The United States Of America 2021, 118: e2014876118. PMID: 33879608, PMCID: PMC8092574, DOI: 10.1073/pnas.2014876118.Peer-Reviewed Original ResearchConceptsMild primary aldosteronismHigh-salt dietPrimary aldosteronismAldosterone productionNormal aldosterone productionPeak intracellular calcium concentrationRenin-angiotensin systemSystolic blood pressureEarly-onset hypertensionAdrenal glomerulosa cellsIntracellular calcium concentrationWild-type littermatesElevated intracellular CaCalcium entry pathwayCorresponding knockout miceFunction mutationsFH-IVPlasma aldosteroneRenin ratioBlood pressureChronic settingAdrenal morphologyZona glomerulosaGlomerulosa cellsAdrenal slicesRho-GTPase Activating Protein myosin MYO9A identified as a novel candidate gene for monogenic focal segmental glomerulosclerosis
Li Q, Gulati A, Lemaire M, Nottoli T, Bale A, Tufro A. Rho-GTPase Activating Protein myosin MYO9A identified as a novel candidate gene for monogenic focal segmental glomerulosclerosis. Kidney International 2021, 99: 1102-1117. PMID: 33412162, PMCID: PMC8076076, DOI: 10.1016/j.kint.2020.12.022.Peer-Reviewed Original ResearchConceptsRhoA activityRho-GAP domainActin stress fiber formationCell junction assemblySmall GTPase proteinsNovel candidate genesStress fiber formationBundles actinCytoskeleton regulationGTPase proteinsActomyosin contractilityJunction assemblyMYO9AAutosomal dominant focal segmental glomerulosclerosisCandidate genesGene contributionCytoskeletal apparatusUnconventional myosinNovel componentRhoA geneWhole-exome sequencingGene editingFSGS phenotypeMolecular causesCalmodulin interaction
2015
Impaired LRP6-TCF7L2 Activity Enhances Smooth Muscle Cell Plasticity and Causes Coronary Artery Disease
Srivastava R, Zhang J, Go GW, Narayanan A, Nottoli TP, Mani A. Impaired LRP6-TCF7L2 Activity Enhances Smooth Muscle Cell Plasticity and Causes Coronary Artery Disease. Cell Reports 2015, 13: 746-759. PMID: 26489464, PMCID: PMC4626307, DOI: 10.1016/j.celrep.2015.09.028.Peer-Reviewed Original ResearchConceptsCoronary artery diseaseLRP6 activityArtery diseaseObstructive coronary artery diseaseHigh-fat dietVascular smooth muscle cell differentiationMuscle cell plasticitySmooth muscle cell differentiationAtherosclerotic burdenMedial hyperplasiaCarotid injuryArterial diseaseVascular obstructionNeointima formationTherapeutic targetWnt3a administrationIntact WntVSMC differentiationKnockout backgroundDiseaseMiceVessel wallNon-canonical WntCoreceptor LRP6Cell plasticity
2013
Dynamic Migration and Cell‐Cell Interactions of Early Reprogramming Revealed by High‐Resolution Time‐Lapse Imaging
Megyola CM, Gao Y, Teixeira AM, Cheng J, Heydari K, Cheng E, Nottoli T, Krause DS, Lu J, Guo S. Dynamic Migration and Cell‐Cell Interactions of Early Reprogramming Revealed by High‐Resolution Time‐Lapse Imaging. Stem Cells 2013, 31: 895-905. PMID: 23335078, PMCID: PMC4309553, DOI: 10.1002/stem.1323.Peer-Reviewed Original ResearchConceptsCell-cell interactionsEarly reprogrammingDynamic cell-cell interactionsSingle-cell resolutionTime-lapse microscopyE-cadherin inhibitionTime-lapse imagingPluripotency inductionInduced pluripotencyGranulocyte-monocyte progenitorsPluripotent cellsReprogrammingMolecular mechanismsCell resolutionCell migrationCellular interactionsGenetic makeupE-cadherinSatellite coloniesExperimental systemHematopoietic stateSource cellsRare cellsColoniesComplex mechanismsKinesin 5B (KIF5B) Is Required for Progression through Female Meiosis and Proper Chromosomal Segregation in Mitotic Cells
Kidane D, Sakkas D, Nottoli T, McGrath J, Sweasy JB. Kinesin 5B (KIF5B) Is Required for Progression through Female Meiosis and Proper Chromosomal Segregation in Mitotic Cells. PLOS ONE 2013, 8: e58585. PMID: 23560038, PMCID: PMC3613343, DOI: 10.1371/journal.pone.0058585.Peer-Reviewed Original ResearchConceptsMitotic cell divisionCell divisionKinesin 5BChromosomal segregationMitotic cellsCell developmentGerminal vesicle breakdownKnockdown of KIF5BProper chromosomal segregationChromosomal segregation defectsFemale meiosisSegregation defectsChromosomal stabilityRNA interferenceChromosomal instabilityFirst polar bodyMouse oocytesKIF5BMolecular motorsPolar bodyVesicle breakdownBirth defectsDivisionCellsMeiosis
2012
Y265C DNA polymerase beta knockin mice survive past birth and accumulate base excision repair intermediate substrates
Senejani AG, Dalal S, Liu Y, Nottoli TP, McGrath JM, Clairmont CS, Sweasy JB. Y265C DNA polymerase beta knockin mice survive past birth and accumulate base excision repair intermediate substrates. Proceedings Of The National Academy Of Sciences Of The United States Of America 2012, 109: 6632-6637. PMID: 22493258, PMCID: PMC3340078, DOI: 10.1073/pnas.1200800109.Peer-Reviewed Original ResearchConceptsDNA polymerase activityWT littermatesKnockin miceMiceMouse embryo fibroblastsChromosomal aberrationsWT mouse embryo fibroblastsNormal Mendelian ratioSlow proliferationPolymerase activityBirthΒ variantCell deathEmbryo fibroblastsWT cellsExcision repair pathwayDNA repair systemsCellular metabolismBase excision repair pathwayFibroblastsHoursHigh levelsHomozygous mutantsKey players
2010
Glucocerebrosidase gene-deficient mouse recapitulates Gaucher disease displaying cellular and molecular dysregulation beyond the macrophage
Mistry PK, Liu J, Yang M, Nottoli T, McGrath J, Jain D, Zhang K, Keutzer J, Chuang WL, Mehal WZ, Zhao H, Lin A, Mane S, Liu X, Peng YZ, Li JH, Agrawal M, Zhu LL, Blair HC, Robinson LJ, Iqbal J, Sun L, Zaidi M. Glucocerebrosidase gene-deficient mouse recapitulates Gaucher disease displaying cellular and molecular dysregulation beyond the macrophage. Proceedings Of The National Academy Of Sciences Of The United States Of America 2010, 107: 19473-19478. PMID: 20962279, PMCID: PMC2984187, DOI: 10.1073/pnas.1003308107.Peer-Reviewed Original ResearchConceptsType 1 Gaucher diseaseThymic T cellsGene-deficient miceOsteoblastic bone formationWorthwhile therapeutic targetDendritic cellsSevere osteoporosisAutoimmune diseasesWidespread dysfunctionCytokine measurementsT cellsCell lineagesParkinson's diseaseTherapeutic targetGBA1 geneMononuclear phagocytesGaucher diseaseGlucocerebrosidase deficiencyMolecular dysregulationDiseaseInhibitory effectBone formationMultiple cell lineagesMesenchymal cell lineagesMacrophages
2008
Chimeric mice reveal clonal development of pancreatic acini, but not islets
Swenson ES, Xanthopoulos J, Nottoli T, McGrath J, Theise ND, Krause DS. Chimeric mice reveal clonal development of pancreatic acini, but not islets. Biochemical And Biophysical Research Communications 2008, 379: 526-531. PMID: 19116141, PMCID: PMC2657659, DOI: 10.1016/j.bbrc.2008.12.104.Peer-Reviewed Original ResearchConceptsStem/progenitor cellsMultiple progenitorsAdult mouse small intestineMale ES cellsProgenitor cellsFemale blastocystsCrypt stem cellsClonal descendantsES cellsY chromosomeChimeric miceFemale cellsIntestinal crypt stem cellsExocrine pancreatic aciniFemale epithelial cellsClonal developmentStem cellsSitu hybridizationMouse small intestineEpithelial cellsIntestinal cryptsProgenitorsPancreatic aciniCellsPancreatic islets
2007
Disruption of cAMP and Prostaglandin E2 Transport by Multidrug Resistance Protein 4 Deficiency Alters cAMP-Mediated Signaling and Nociceptive Response
Lin ZP, Zhu YL, Johnson DR, Rice KP, Nottoli T, Hains BC, McGrath J, Waxman SG, Sartorelli AC. Disruption of cAMP and Prostaglandin E2 Transport by Multidrug Resistance Protein 4 Deficiency Alters cAMP-Mediated Signaling and Nociceptive Response. Molecular Pharmacology 2007, 73: 243-251. PMID: 17959714, PMCID: PMC2780335, DOI: 10.1124/mol.107.039594.Peer-Reviewed Original ResearchConceptsNociceptive responsesPG synthesisInflammatory nociceptive responsesInflammatory pain thresholdWild-type miceCyclooxygenase-2 expressionMrp4 knockout miceMultidrug resistance protein 4Accumulation of intracellularMEF cellsMRP4 knockdownNucleotide agentsPain thresholdDisruptions of cAMPPGE metabolitePG levelsEnergy-dependent effluxProtein 4MiceMRP4PG transportIntracellular levelsProstaglandinsATP-binding cassette (ABC) familyPronounced reduction
2006
Abolished cocaine reward in mice with a cocaine-insensitive dopamine transporter
Chen R, Tilley MR, Wei H, Zhou F, Zhou FM, Ching S, Quan N, Stephens RL, Hill ER, Nottoli T, Han DD, Gu HH. Abolished cocaine reward in mice with a cocaine-insensitive dopamine transporter. Proceedings Of The National Academy Of Sciences Of The United States Of America 2006, 103: 9333-9338. PMID: 16754872, PMCID: PMC1482610, DOI: 10.1073/pnas.0600905103.Peer-Reviewed Original ResearchConceptsRole of DATFunctional dopamine transporterDopamine transporterCocaine rewardSerotonin transporterNorepinephrine transporterExtracellular DAKnockout miceCocaine-insensitive dopamine transporterRole of NETNET knockout miceDAT knockout miceSelf-administer cocaineKnockin mouse lineMouse modelNucleus accumbensDopamine hypothesisPlace preferenceDA hypothesisLocomotor activityReward pathwayBehavioral effectsMiceMouse linesCalcium oxalate urolithiasis in mice lacking anion transporter Slc26a6
Jiang Z, Asplin JR, Evan AP, Rajendran VM, Velazquez H, Nottoli TP, Binder HJ, Aronson PS. Calcium oxalate urolithiasis in mice lacking anion transporter Slc26a6. Nature Genetics 2006, 38: 474-478. PMID: 16532010, DOI: 10.1038/ng1762.Peer-Reviewed Original ResearchConceptsCalcium oxalate urolithiasisOxalate urolithiasisPlasma oxalate concentrationIntestinal oxalate secretionUrinary oxalate concentrationCommon urologic diseaseNet intestinal absorptionAnion exchanger SLC26A6Dietary oxalate restrictionSlc26a6-null miceSignificant hyperoxaluriaOxalate restrictionUrologic diseasesHigh incidenceIntestinal absorptionExchanger SLC26A6Mutant miceUrolithiasisMiceMajor constitutive roleNet absorptionOxalate secretionHyperoxaluriaOxalate concentrationEpithelial tissues
2003
Positive influence of AP-2α transcription factor on cadherin gene expression and differentiation of the ocular surface
West-Mays J, Sivak J, Papagiotas S, Kim J, Nottoli T, Williams T, Fini M. Positive influence of AP-2α transcription factor on cadherin gene expression and differentiation of the ocular surface. Differentiation 2003, 71: 206-216. PMID: 12694203, PMCID: PMC2517417, DOI: 10.1046/j.1432-0436.2003.710302.x.Peer-Reviewed Original Research
2002
Transcription factor AP-2gamma is essential in the extra-embryonic lineages for early postimplantation development.
Auman HJ, Nottoli T, Lakiza O, Winger Q, Donaldson S, Williams T. Transcription factor AP-2gamma is essential in the extra-embryonic lineages for early postimplantation development. Development 2002, 129: 2733-47. PMID: 12015300, DOI: 10.1242/dev.129.11.2733.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlastocystBreast NeoplasmsDNA-Binding ProteinsEmbryo ImplantationEmbryonic and Fetal DevelopmentFemaleGene Expression Regulation, DevelopmentalGenotypeHumansMiceMice, KnockoutMorphogenesisPlacentaPolymerase Chain ReactionPregnancyRestriction MappingTranscription Factor AP-2Transcription FactorsConceptsExtra-embryonic lineagesAP-2gammaAnterior-posterior patterningStem cell maintenanceEarly postimplantation developmentExtra-embryonic tissuesAcid-responsive genesAP-2 familyRetinoic acid-responsive geneTrophoblast-specific expressionMaternal-embryonic interfaceMammalian developmentDays post coitumExtra-embryonic membranesCell maintenanceTranscription factorsEmbryonic developmentGene disruptionBiological functionsMouse embryosPostimplantation developmentPreimplantation embryosMutantsMolecular analysisNormal development
1999
AP-2αTranscription Factor Is Required for Early Morphogenesis of the Lens Vesicle
West-Mays J, Zhang J, Nottoli T, Hagopian-Donaldson S, Libby D, Strissel K, Williams T. AP-2αTranscription Factor Is Required for Early Morphogenesis of the Lens Vesicle. Developmental Biology 1999, 206: 46-62. PMID: 9918694, DOI: 10.1006/dbio.1998.9132.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnimals, NewbornAquaporinsChimeraDNA-Binding ProteinsEyeEye ProteinsGene Expression Regulation, DevelopmentalHistocytochemistryHomeodomain ProteinsImmunohistochemistryLens, CrystallineMembrane GlycoproteinsMiceMice, KnockoutMorphogenesisPaired Box Transcription FactorsPAX6 Transcription FactorPhenotypeRepressor ProteinsTranscription Factor AP-2Transcription FactorsConceptsOcular defectsGanglion cell layerAP-2alphaRetinoic acid-responsive geneNeural retinaChimeric miceOcular tissuesOcular phenotypeDorsal retinalOptic cupCell layerLens vesicleAP-2 transcription factorsEyesEarly morphogenesisSurface ectodermLens developmentKnockout embryosCurrent studyAP-2 proteinsAcid-responsive genesExpression patternsPersistent adhesionTranscription factorsComplete lack
1998
AP-2-null cells disrupt morphogenesis of the eye, face, and limbs in chimeric mice
Nottoli T, Hagopian-Donaldson S, Zhang J, Perkins A, Williams T. AP-2-null cells disrupt morphogenesis of the eye, face, and limbs in chimeric mice. Proceedings Of The National Academy Of Sciences Of The United States Of America 1998, 95: 13714-13719. PMID: 9811866, PMCID: PMC24885, DOI: 10.1073/pnas.95.23.13714.Peer-Reviewed Original ResearchConceptsAP-2Neural tubePleiotropic developmental abnormalitiesAP-2 geneCritical new roleLimb pattern formationRange of phenotypesBody wallLethal phenotypeKnockout miceMorphogenic pathwaysChimeric miceEye formationDevelopmental mechanismsHomozygous disruptionLimb duplicationsTeratogenic levelsDefective developmentDevelopmental abnormalitiesRetinoic acidPhenotypeMechanism of actionIndependent requirementsPattern formationChimeras