2025
Physiologic mechanisms underlying polycystic kidney disease
Boletta A, Caplan M. Physiologic mechanisms underlying polycystic kidney disease. Physiological Reviews 2025, 105: 1553-1607. PMID: 39938884, PMCID: PMC12174308, DOI: 10.1152/physrev.00018.2024.Peer-Reviewed Original ResearchPrimary ciliaPolycystic kidney diseaseTrafficking of proteinsHuman ciliopathiesExtracellular signalsMultiple genesKidney diseaseProtein productionMolecular basisCell biologyMonogenic disordersCyst formationGenesRenal epithelial cellsProteinCiliaBiochemical informationApical surfaceEpithelial cellsFunctional expressionPhysiological propertiesWealth of informationPhysiological mechanismsCellsFibrocystin
2024
Cilia structure and intraflagellar transport differentially regulate sensory response dynamics within and between C. elegans chemosensory neurons
Philbrook A, O’Donnell M, Grunenkovaite L, Sengupta P. Cilia structure and intraflagellar transport differentially regulate sensory response dynamics within and between C. elegans chemosensory neurons. PLOS Biology 2024, 22: e3002892. PMID: 39591402, PMCID: PMC11593760, DOI: 10.1371/journal.pbio.3002892.Peer-Reviewed Original ResearchConceptsIntraflagellar transportOrganization of signaling moleculesASH nociceptive neuronsAWA olfactory neuronsCiliary traffickingNociceptive neuronsCilia baseOlfactory neuronsCaenorhabditis elegansOdor responsesSignaling proteinsCilia organizationSensory neuronsCilium structurePrimary ciliaCilia structureSignaling moleculesAcute inhibitionSegregation of receptorsRegulation of responsesChemosensory neuronsNeuron typesCilium lengthNeuronal responsesEctopic branchingFunctional Evaluation of a Novel Homozygous ADCY3 Variant Causing Childhood Obesity
Mohammed I, Selvaraj S, Ahmed W, Al-Barazenji T, Dauleh H, Love D, Saraiva L, Hussain K. Functional Evaluation of a Novel Homozygous ADCY3 Variant Causing Childhood Obesity. International Journal Of Molecular Sciences 2024, 25: 11815. PMID: 39519366, PMCID: PMC11547096, DOI: 10.3390/ijms252111815.Peer-Reviewed Original ResearchAdenylate cyclase 3Early-onset obesityRegulating various downstream signaling pathwaysIn silico functional characterizationHomozygous nonsense variant c.Homozygous loss-of-function variantsIn silico functional analysisLoss-of-function variantsReceptor loss of functionNonsense variant c.Impaired enzymatic activityGene panel sequencingATP to cAMPIn silico validationDownstream signaling pathwaysGain-of-function variantsPrimary cilia of neuronsIn vitroInsulin resistanceLoss of functionTransmembrane proteinsFunctional characterizationPrimary ciliaNovel p.Variant c.Structure, interaction and nervous connectivity of beta cell primary cilia
Müller A, Klena N, Pang S, Garcia L, Topcheva O, Aurrecoechea Duran S, Sulaymankhil D, Seliskar M, Mziaut H, Schöniger E, Friedland D, Kipke N, Kretschmar S, Münster C, Weitz J, Distler M, Kurth T, Schmidt D, Hess H, Xu C, Pigino G, Solimena M. Structure, interaction and nervous connectivity of beta cell primary cilia. Nature Communications 2024, 15: 9168. PMID: 39448638, PMCID: PMC11502866, DOI: 10.1038/s41467-024-53348-5.Peer-Reviewed Original ResearchConceptsPrimary ciliaCell's primary ciliumNon-islet cellsPancreatic beta cellsCiliary pocketSensory organellesAxonemal organizationMotility componentsExtrinsic signalsStructural basisBeta cellsCiliaCell typesExpansion microscopyParacrine signalingIslet innervationCellsIsletsBetaAxonemeOrganellesSignalThree-dimensional reconstructionInteractionLateral 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 bodiesGlis2 is an early effector of polycystin signaling and a target for therapy in polycystic kidney disease
Zhang C, Rehman M, Tian X, Pei S, Gu J, Bell T, Dong K, Tham M, Cai Y, Wei Z, Behrens F, Jetten A, Zhao H, Lek M, Somlo S. Glis2 is an early effector of polycystin signaling and a target for therapy in polycystic kidney disease. Nature Communications 2024, 15: 3698. PMID: 38693102, PMCID: PMC11063051, DOI: 10.1038/s41467-024-48025-6.Peer-Reviewed Original ResearchConceptsMouse models of autosomal dominant polycystic kidney diseaseModel of autosomal dominant polycystic kidney diseasePolycystin signalingAutosomal dominant polycystic kidney diseasePolycystin-1Polycystic kidney diseaseTreat autosomal dominant polycystic kidney diseaseGlis2Primary ciliaKidney tubule cellsSignaling pathwayMouse modelDominant polycystic kidney diseasePotential therapeutic targetTranslatomeAntisense oligonucleotidesKidney diseasePolycystinMouse kidneyFunctional effectorsCyst formationTherapeutic targetInactivationFunctional targetPharmacological targetsCellular Mechanisms Underlying the Pathogenetic Role of the Primary Cilium in Pulmonary Arterial Hypertension
Melnikov A, Solymosi P, Pennitz P, Schupp J, Nouailles G, Perret P, Gallo K, Hegemann N, Nambiar Veetil N, Klepetko W, Sinn K, Erfinanda L, Simmons S, Kucherenko M, Knosalla C, Preissner R, Kwapiszewska G, Witzenrath M, Kuebler W. Cellular Mechanisms Underlying the Pathogenetic Role of the Primary Cilium in Pulmonary Arterial Hypertension. 2024, a6790-a6790. DOI: 10.1164/ajrccm-conference.2024.209.1_meetingabstracts.a6790.Peer-Reviewed Original ResearchUnraveling cellular complexity with transient adapters in highly multiplexed super-resolution imaging
Schueder F, Rivera-Molina F, Su M, Marin Z, Kidd P, Rothman J, Toomre D, Bewersdorf J. Unraveling cellular complexity with transient adapters in highly multiplexed super-resolution imaging. Cell 2024, 187: 1769-1784.e18. PMID: 38552613, PMCID: PMC12135969, DOI: 10.1016/j.cell.2024.02.033.Peer-Reviewed Original ResearchConceptsInter-organelle contactsSuper-resolutionMultiplexed super-resolution microscopyIntricate spatial relationshipsGolgi stacksMammalian cellsCellular functionsSuper-resolution microscopyPrimary ciliaSuper-resolution fluorescence microscopyCellular complexityTransient adaptationFluorescence microscopyDNA-PAINTFluorogenic labelingMolecular targetsSpatial relationshipsImagesThroughput
2023
Pathogenic RAB34 variants impair primary cilium assembly and cause a novel oral-facial-digital syndrome
Bruel A, Ganga A, Nosková L, Valenzuela I, Martinovic J, Duffourd Y, Zikánová M, Majer F, Kmoch S, Mohler M, Sun J, Sweeney L, Martínez-Gil N, Thauvin-Robinet C, Breslow D. Pathogenic RAB34 variants impair primary cilium assembly and cause a novel oral-facial-digital syndrome. Human Molecular Genetics 2023, 32: 2822-2831. PMID: 37384395, PMCID: PMC10481091, DOI: 10.1093/hmg/ddad109.Peer-Reviewed Original ResearchConceptsCilia assemblyCiliary membrane formationIntracellular ciliogenesis pathwayPrimary cilia assemblyBi-allelic missense variantsRab proteinsRab GTPaseCiliary proteinsSmall GTPaseNascent ciliaMother centriolePrimary ciliaC-terminusProtein productsPathogenic variantsRab34Cell typesFunctional impactMissense variantsGTPaseStrong lossCiliogenesisSignificant defectsGenesKey mediator
2022
XBP1 Activation Reduces Severity of Polycystic Kidney Disease due to a Nontruncating Polycystin-1 Mutation in Mice
Krappitz M, Bhardwaj R, Dong K, Staudner T, Yilmaz DE, Pioppini C, Westergerling P, Ruemmele D, Hollmann T, Nguyen TA, Cai Y, Gallagher AR, Somlo S, Fedeles S. XBP1 Activation Reduces Severity of Polycystic Kidney Disease due to a Nontruncating Polycystin-1 Mutation in Mice. Journal Of The American Society Of Nephrology 2022, 34: 110-121. PMID: 36270750, PMCID: PMC10101557, DOI: 10.1681/asn.2021091180.Peer-Reviewed Original ResearchConceptsPolycystin-1Polycystin-2Functional polycystin-1Amino acid substitution mutationsAutosomal dominant polycystic kidney diseaseIntegral membrane proteinsTranscription factor XBP1Unfolded protein responsePost-translational maturationAcid substitution mutationsEndoplasmic reticulum chaperoneCiliary traffickingXBP1 activityChaperone functionIntegral membraneActive XBP1Polycystic kidney diseaseMembrane proteinsPC1 functionsPrimary ciliaProtein responseHypomorphic mutationsTransgenic activationSubstitution mutationsTransgenic expressionA serotonergic axon-cilium synapse drives nuclear signaling to alter chromatin accessibility
Sheu SH, Upadhyayula S, Dupuy V, Pang S, Deng F, Wan J, Walpita D, Pasolli HA, Houser J, Sanchez-Martinez S, Brauchi SE, Banala S, Freeman M, Xu CS, Kirchhausen T, Hess HF, Lavis L, Li Y, Chaumont-Dubel S, Clapham DE. A serotonergic axon-cilium synapse drives nuclear signaling to alter chromatin accessibility. Cell 2022, 185: 3390-3407.e18. PMID: 36055200, PMCID: PMC9789380, DOI: 10.1016/j.cell.2022.07.026.Peer-Reviewed Original ResearchConceptsCA1 pyramidal neuronsChromatin accessibilityPyramidal neuronsSerotonergic axonsEpigenetic statePrimary ciliaHippocampal CA1 pyramidal neuronsChemogenetic stimulationSerotonin receptorsNuclear actinReceptor 6Histone acetylationAxonsChemical synapsesIntercellular communicationRhoA pathwaySynapseNeuronsCiliaSynapsesStimulationPathwayNeurotransmissionReceptorsNon-cell-autonomous activation of hedgehog signaling contributes to disease progression in a mouse model of renal cystic ciliopathy
Hsieh CL, Jerman SJ, Sun Z. Non-cell-autonomous activation of hedgehog signaling contributes to disease progression in a mouse model of renal cystic ciliopathy. Human Molecular Genetics 2022, 31: 4228-4240. PMID: 35904445, PMCID: PMC9759329, DOI: 10.1093/hmg/ddac175.Peer-Reviewed Original ResearchConceptsHh pathwayAutonomous activationMesenchymal cellsPolycystic kidney diseaseEpithelial cellsCre miceGli inhibitor GANT61Reporter mouse linePrimary ciliaHH signalingHedgehog signalingPKD pathogenesisArl13bSonic hedgehogMutant kidneysPKD modelPKD progressionHh activationKidney functionKidney diseaseCyst progressionCo-culture systemMouse linesMouse modelDistal nephron
2021
Rab34 GTPase mediates ciliary membrane formation in the intracellular ciliogenesis pathway
Ganga AK, Kennedy MC, Oguchi ME, Gray S, Oliver KE, Knight TA, De La Cruz EM, Homma Y, Fukuda M, Breslow DK. Rab34 GTPase mediates ciliary membrane formation in the intracellular ciliogenesis pathway. Current Biology 2021, 31: 2895-2905.e7. PMID: 33989527, PMCID: PMC8282722, DOI: 10.1016/j.cub.2021.04.075.Peer-Reviewed Original ResearchConceptsIntracellular pathwaysCiliary membrane biogenesisCiliary membrane formationIntracellular ciliogenesis pathwayMDCK cellsPolarized MDCK cellsDistinct molecular requirementsPrimary cilia formExtracellular pathwaysTissue-specific mannerCiliary pocketGTPase domainMembrane biogenesisDistinct functional propertiesCiliary vesiclesAssembly intermediatesCilia formSignal transductionGTP bindingMother centriolePrimary ciliaCiliogenesisDivergent residuesIntracellular ciliaRab34
2020
Disrupting polycystin-2 EF hand Ca2+ affinity does not alter channel function or contribute to polycystic kidney disease
Vien TN, Ng LCT, Smith JM, Dong K, Krappitz M, Gainullin VG, Fedeles S, Harris PC, Somlo S, DeCaen PG. Disrupting polycystin-2 EF hand Ca2+ affinity does not alter channel function or contribute to polycystic kidney disease. Journal Of Cell Science 2020, 133: jcs255562. PMID: 33199522, PMCID: PMC7774883, DOI: 10.1242/jcs.255562.Peer-Reviewed Original ResearchConceptsAutosomal dominant polycystic kidney diseasePolycystic kidney diseaseKidney diseaseDominant polycystic kidney diseaseChannel functionPhysiological membrane potentialsPolycystin-2Primary ciliaDuct cellsNew mouseChannel activityDiseaseIon channelsDistinct mutationsInternal CaMembrane potentialChannel regulationHand associationEF-hand Ca2Regulatory mechanismsMutationsMicePolycystin 2 is increased in disease to protect against stress-induced cell death
Brill AL, Fischer TT, Walters JM, Marlier A, Sewanan LR, Wilson PC, Johnson EK, Moeckel G, Cantley LG, Campbell SG, Nerbonne JM, Chung HJ, Robert ME, Ehrlich BE. Polycystin 2 is increased in disease to protect against stress-induced cell death. Scientific Reports 2020, 10: 386. PMID: 31941974, PMCID: PMC6962458, DOI: 10.1038/s41598-019-57286-x.Peer-Reviewed Original ResearchConceptsPolycystin-2General cellular homeostasisCell deathStress-induced cell deathPathological cell deathAutosomal dominant polycystic kidney diseaseEndoplasmic reticulum membraneCellular homeostasisCellular stressPrimary ciliaUbiquitous expressionExpression changesCell stressReticulum membraneTransient receptor potential cation channelHuman diseasesMultiple tissuesEndogenous roleDominant polycystic kidney diseaseTissue typesCation channelsPolycystic kidney diseaseDifferent pathological statesMultiple diseasesKidney disease
2019
Cell-Autonomous Hedgehog Signaling Is Not Required for Cyst Formation in Autosomal Dominant Polycystic Kidney Disease
Ma M, Legué E, Tian X, Somlo S, Liem KF. Cell-Autonomous Hedgehog Signaling Is Not Required for Cyst Formation in Autosomal Dominant Polycystic Kidney Disease. Journal Of The American Society Of Nephrology 2019, 30: 2103-2111. PMID: 31451534, PMCID: PMC6830786, DOI: 10.1681/asn.2018121274.Peer-Reviewed Original ResearchConceptsHedgehog pathwayPolycystin-1Polycystin-2Autosomal dominant polycystic kidney diseaseMain causal genePolycystic kidney diseaseKidney cyst formationEpithelial cellsLevels of HedgehogCiliary genesDominant polycystic kidney diseaseMutant mouse kidneysRenal epithelial cellsCausal genesSignal transductionCell signalingGenetic manipulationPrimary ciliaCyst formationMultipass transmembraneHedgehog signalingConditional inactivationUnknown pathwayHedgehogKidney phenotype
2018
Newly synthesized polycystin‐1 takes different trafficking pathways to the apical and ciliary membranes
Gilder AL, Chapin HC, Padovano V, Hueschen CL, Rajendran V, Caplan MJ. Newly synthesized polycystin‐1 takes different trafficking pathways to the apical and ciliary membranes. Traffic 2018, 19: 933-945. PMID: 30125442, PMCID: PMC6237641, DOI: 10.1111/tra.12612.Peer-Reviewed Original ResearchConceptsPolycystin-1Ciliary deliveryBrefeldin AApical deliveryRenal epithelial cellsN-terminal fragmentPolycystin-2LLC-PK1 renal epithelial cellsDifferent trafficking pathwaysTrans-Golgi networkApical membraneEpithelial cellsCultured epithelial cellsTrafficking pathwaysTransmembrane proteinGolgi compartmentPrimary ciliaC-terminal fragmentCiliary membraneC-terminusAutocatalytic cleavageDistinct pathwaysIncubating cellsCell membraneAutosomal dominant polycystic kidney diseaseA CRISPR-based screen for Hedgehog signaling provides insights into ciliary function and ciliopathies
Breslow DK, Hoogendoorn S, Kopp AR, Morgens DW, Vu BK, Kennedy MC, Han K, Li A, Hess GT, Bassik MC, Chen JK, Nachury MV. A CRISPR-based screen for Hedgehog signaling provides insights into ciliary function and ciliopathies. Nature Genetics 2018, 50: 460-471. PMID: 29459677, PMCID: PMC5862771, DOI: 10.1038/s41588-018-0054-7.Peer-Reviewed Original ResearchConceptsFunctional genomic screensGenome-wide CRISPRCiliary functionHedgehog-responsive cellsCiliary signalingΕ-tubulinProtein complexesGenomic screenEmbryonic developmentGene disruptionPrimary ciliaΔ-tubulinNovel componentCiliopathiesCRISPRCiliary structureUnbiased toolHedgehogUnifying causeScreenGenesSignalingCiliaSystematic analysisPathway
2017
Adenylyl cyclase 5 deficiency reduces renal cyclic AMP and cyst growth in an orthologous mouse model of polycystic kidney disease
Wang Q, Cobo-Stark P, Patel V, Somlo S, Han PL, Igarashi P. Adenylyl cyclase 5 deficiency reduces renal cyclic AMP and cyst growth in an orthologous mouse model of polycystic kidney disease. Kidney International 2017, 93: 403-415. PMID: 29042084, PMCID: PMC5794572, DOI: 10.1016/j.kint.2017.08.005.Peer-Reviewed Original ResearchConceptsPolycystic kidney diseaseOrthologous mouse modelSingle mutant miceMutant miceRenal epithelial cellsCyst growthCAMP levelsKidney diseaseEpithelial cellsMouse modelTreatment of PKDA-kinase anchoring protein 150Renal cyclic AMPKidneys of miceCyclic AMPDouble mutant miceRenal cAMP levelsInhibition of AC5Kidney injuryLevels of cAMPPrimary ciliaKidney enlargementKidney functionCyst indexMicePalmitoylation of the ciliary GTPase ARL13b is necessary for its stability and its role in cilia formation
Roy K, Jerman S, Jozsef L, McNamara T, Onyekaba G, Sun Z, Marin EP. Palmitoylation of the ciliary GTPase ARL13b is necessary for its stability and its role in cilia formation. Journal Of Biological Chemistry 2017, 292: 17703-17717. PMID: 28848045, PMCID: PMC5663873, DOI: 10.1074/jbc.m117.792937.Peer-Reviewed Original ResearchConceptsPost-translational attachmentMost mammalian cellsCiliary GTPase Arl13bCilia localizationProtein palmitoylationCiliary proteinsCilia proteinsProtein localizationCilia formationMammalian cellsCilia functionPalmitoylationPrimary ciliaPlasma membraneCilia resorptionArl13bFunctional importanceMyristoylationCiliaCritical roleProteinMouse kidneyLocalizationDepalmitoylationCells
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