Timothy Nottoli, PhD
Senior Research Scientist in Comparative MedicineCards
About
Research
Publications
2025
Cell-type-specific dysregulation of gene expression due to Chd8 haploinsufficiency during mouse cortical development
Yim K, Baumgartner M, Krenzer M, Rosales Larios M, Hill-Terán G, Nottoli T, Muhle R, Noonan J. Cell-type-specific dysregulation of gene expression due to Chd8 haploinsufficiency during mouse cortical development. Cell Genomics 2025, 100986. PMID: 40967226, DOI: 10.1016/j.xgen.2025.100986.Peer-Reviewed Original ResearchCHD8 haploinsufficiencyGenes associated with neurodevelopmental disordersExcitatory cortical neuronsAssociated with riskRisk-associated genesSingle-nucleus RNA sequencingEmbryonic radial gliaNeurodevelopmental gene expressionNeuron projection developmentCortical plateDisruptive variantsImpaired synaptogenesisChromatin remodelingSynaptic activityMouse cortical developmentMature neuronsCortical developmentNeuronal lineageHaploinsufficiencyCortical neuronsRNA sequencingSingle-nucleusProgenitor zoneGene expressionRadial gliaHeterozygosity for neurodevelopmental disorder-associated TRIO variants yields distinct deficits in behavior, neuronal development, and synaptic transmission in mice
Ishchenko Y, Jeng A, Feng S, Nottoli T, Manriquez-Rodriguez C, Nguyen K, Carrizales M, Vitarelli M, Corcoran E, Greer C, Myers S, Koleske A. Heterozygosity for neurodevelopmental disorder-associated TRIO variants yields distinct deficits in behavior, neuronal development, and synaptic transmission in mice. ELife 2025, 13: rp103620. PMID: 40488445, PMCID: PMC12148328, DOI: 10.7554/elife.103620.Peer-Reviewed Original ResearchConceptsAutism spectrum disorderGuanine nucleotide exchange factorNeurodevelopmental disordersPresynaptic glutamate releaseLayer 5 pyramidal neuronsAssociated with neurodevelopmental disordersIntellectual disabilitySpectrum disorderMouse behaviorCognitive behaviorNucleotide exchange factorNeuronal developmentBrain developmentGlutamate releaseIncreased Rac1 activityBrain sizeSynaptic functionControlling neuronal developmentSchizophreniaImpaired abilityAssociated with increased levelsNeurodevelopmental eventsActive GTPaseGEF Tiam1Exchange factorHeterozygosity for neurodevelopmental disorder-associated TRIO variants yields distinct deficits in behavior, neuronal development, and synaptic transmission in mice
Ishchenko Y, Jeng A, Feng S, Nottoli T, Manriquez-Rodriguez C, Nguyen K, Carrizales M, Vitarelli M, Corcoran E, Greer C, Myers S, Koleske A. Heterozygosity for neurodevelopmental disorder-associated TRIO variants yields distinct deficits in behavior, neuronal development, and synaptic transmission in mice. ELife 2025, 13 DOI: 10.7554/elife.103620.3.Peer-Reviewed Original ResearchAutism spectrum disorderGuanine nucleotide exchange factorNeurodevelopmental disordersPresynaptic glutamate releaseLayer 5 pyramidal neuronsAssociated with neurodevelopmental disordersIntellectual disabilitySpectrum disorderMouse behaviorCognitive behaviorNucleotide exchange factorSchizophreniaNeuronal developmentBrain developmentGlutamate releaseIncreased Rac1 activityBrain sizeSynaptic functionControlling neuronal developmentImpaired abilityAssociated with increased levelsNeurodevelopmental eventsActive GTPaseGEF Tiam1Exchange factorCas12a-knock-in mice for multiplexed genome editing, disease modelling and immune-cell engineering
Tang K, Zhou L, Tian X, Fang S, Vandenbulcke E, Du A, Shen J, Cao H, Zhou J, Chen K, Kim H, Luo Z, Xin S, Lin S, Park D, Yang L, Zhang Y, Suzuki K, Majety M, Ling X, Lam S, Chow R, Ren P, Tao B, Li K, Codina A, Dai X, Shang X, Bai S, Nottoli T, Levchenko A, Booth C, Liu C, Fan R, Dong M, Zhou X, Chen S. Cas12a-knock-in mice for multiplexed genome editing, disease modelling and immune-cell engineering. Nature Biomedical Engineering 2025, 9: 1290-1308. PMID: 40114032, PMCID: PMC12360953, DOI: 10.1038/s41551-025-01371-2.Peer-Reviewed Original ResearchKnock-In MiceBone marrow-derived dendritic cellsCD8+ T cellsNon-viral delivery vehiclesAdeno-associated virusDisease modelsCD4+Dendritic cellsC57BL/6 backgroundT cellsConstitutive expressionB cellsLipid nanoparticlesEx vivoGenome editingMiceMultiplex genome engineeringROSA26 locusGene interaction networksMultiplex genome editingLiver tissueTargeted genome editingDiseaseDelivery vehiclesCRISPR RNA
2024
65 High-fidelity enhanced AsCas12a knock-in mice for efficient multiplexed gene editing, disease modeling and orthogonal immunogenetics
Tang K, Zhou X, Fang S, Vandenbulcke E, Du A, Shen J, Cao H, Zhou J, Chen K, Xin S, Zhou L, Lin S, Majety M, Lin X, Lam S, Chow R, Bai S, Nottoli T, Booth C, Liu C, Dong M, Chen S. 65 High-fidelity enhanced AsCas12a knock-in mice for efficient multiplexed gene editing, disease modeling and orthogonal immunogenetics. 2024, a72-a72. DOI: 10.1136/jitc-2024-sitc2024.0065.Peer-Reviewed Original ResearchEvolutionary Innovations in Conserved Regulatory Elements Associate With Developmental Genes in Mammals
Uebbing S, Kocher A, Baumgartner M, Ji Y, Bai S, Xing X, Nottoli T, Noonan J. Evolutionary Innovations in Conserved Regulatory Elements Associate With Developmental Genes in Mammals. Molecular Biology And Evolution 2024, 41: msae199. PMID: 39302728, PMCID: PMC11465374, DOI: 10.1093/molbev/msae199.Peer-Reviewed Original ResearchSequence evolutionRegulatory evolutionDevelopmental signaling genesEnhanced evolutionEvolutionary innovationMammalian phylogenyTranscriptional enhancersGenetic variationPhenotypic variationPleiotropic genesDevelopmental genesEnhancer elementsHoofed mammalsEnhancer sequencesActivation domainSignaling GenesEvolutionary adaptationDiverse organismsGenesHuman diseasesRegulatory functionsDevelopmental processesDeveloping limbCell typesMammalsCellular stiffness sensing through talin 1 in tissue mechanical homeostasis
Chanduri M, Kumar A, Weiss D, Emuna N, Barsukov I, Shi M, Tanaka K, Wang X, Datye A, Kanyo J, Collin F, Lam T, Schwarz U, Bai S, Nottoli T, Goult B, Humphrey J, Schwartz M. Cellular stiffness sensing through talin 1 in tissue mechanical homeostasis. Science Advances 2024, 10: eadi6286. PMID: 39167642, PMCID: PMC11338229, DOI: 10.1126/sciadv.adi6286.Peer-Reviewed Original ResearchConceptsTissue mechanical homeostasisStiffness sensingExtracellular matrixTalin-1Mechanical homeostasisExtracellular matrix mechanicsIncreased cell spreadingCell spreadingTalinMutationsCellular sensingFibrillar collagenReduced axial stiffnessTissue mechanical propertiesMechanical propertiesAxial stiffnessCompliant substratesHomeostasisRupture pressureArp2/3ARPC5LStiffnessHomeostasis hypothesisResident cellsTissue stiffnessCpG 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
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