Zhaoxia Sun, PhD
Cards
Appointments
Titles
Co-Director of Graduate Studies, Genetics
Contact Info
Appointments
Titles
Co-Director of Graduate Studies, Genetics
Contact Info
Appointments
Titles
Co-Director of Graduate Studies, Genetics
Contact Info
About
Titles
Associate Professor of Genetics
Co-Director of Graduate Studies, GeneticsAppointments
Genetics
Associate Professor TenurePrimary
Other Departments & Organizations
Education & Training
- postdoctoral associate
- MIT (2003)
- PhD
- Yale University School of Medicine (1998)
Research
Overview
The cilium is a hair like cell surface organelle that is almost ubiquitously present on vertebrate cells. While motile cilia beat to propel cell movement or fluid flow over the cell surface, immotile cilia function as cellular antennae that detect extracellular signals and couple them to cellular responses. Cilia dysgenesis and dysfunction have been linked to a growing list of human diseases ranging from polycystic kidney disease (PKD), cancer, to mental retardation and obesity, collectively referred to as ciliopathies. However, the cilium is also one of the few organelles whose physiology and function remain to be fully interrogated. Despite the amazing structural conservation of this organelle from green algae to human, the function of the cilium has diverged significantly between vertebrates and traditional invertebrate model organisms, including Drosophila and C. elegans.
In contrast to fly and worm, zebrafish shows significant functional conservation of cilia-mediated signaling with mammals. Combined with its amenability to large-scale chemical and genetic screens, the accessibility of cilia in multiple organs and the collection of cilia mutants already available, this feature of zebrafish makes it uniquely positioned as a model system for studying cilia and ciliopathy. Complementary to the zebrafish system, mouse is a mammalian model suitable for validation of functional conservation and translational research.
Originally founded as the first zebrafish lab in Yale School of Medicine, our research has expanded into mouse and cell culture systems. We are striving to tease out the mechanisms that govern cilia biogenesis, motility and size and the role of cilia in development and diseases. One disease of particular interest is polycystic kidney disease (PKD). PKD is characterized by the formation of multiple kidney cysts thought to result from over-proliferation of epithelial cells. Understanding PKD is of profound medical importance. Striking one in 1000 live births, autosomal dominant form of PKD (ADPKD) is among the most common monogenetic disorders in humans. Our studies have provided strong evidence for the critical role of the cilium in PKD pathogenesis and suggested HDAC inhibitors as promising candidate drugs for treating PKD. More recently we demonstrated the role of epithelial-stromal crosstalk in cyst formation and interstitial fibrosis in renal ciliopathies.
In addition, we are studying a motile ciliopathy called primary ciliary dyskinesia (PCD), characterized by chronic pulmonary infection and can progress to respiratory failure if unmanaged. By collaborating with human genetic groups, we contributed to the identification of PIH1D3 as a gene associated with PCD. We discovered the critical role of Ruvbl1/Pontin and Ruvbl2/Reptin in building dynein arms, the macromolecular machine that powers cilia motility, and showed that they co-localize to droplet like cytosolic foci together with the dynein arm assembly factor Lrrc6, and our recent findings point to novel mechanisms for building dynein arms at scale.
Medical Subject Headings (MeSH)
Research at a Glance
Yale Co-Authors
Publications Timeline
Research Interests
Yuanyuan Li, PhD
David F. Stern, PhD
Martina Brueckner, MD
Michael Caplan, PhD, MD
Ronald Coifman, PhD
Erdem Karatekin, PhD
Zebrafish
Kidney
Polycystic Kidney Diseases
Kartagener Syndrome
Ciliopathies
Fibrosis
Publications
2023
Epithelial-Mesenchymal Cross-Talks in Murine Models of Renal Ciliopathy
Sun Z, Hsieh C, Li Y, Xu W, Makova S, Brueckner M. Epithelial-Mesenchymal Cross-Talks in Murine Models of Renal Ciliopathy. Journal Of The American Society Of Nephrology 2023, 34: 563-563. DOI: 10.1681/asn.20233411s1563a.Peer-Reviewed Original ResearchInactivation of Invs/Nphp2 in renal epithelial cells drives infantile nephronophthisis like phenotypes in mouse
Li Y, Xu W, Makova S, Brueckner M, Sun Z. Inactivation of Invs/Nphp2 in renal epithelial cells drives infantile nephronophthisis like phenotypes in mouse. ELife 2023, 12: e82395. PMID: 36920028, PMCID: PMC10154023, DOI: 10.7554/elife.82395.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsFlox/Valproic acidRenal fibrosisCyst formationEnd-stage renal diseaseMutant miceHistone deacetylase inhibitor valproic acidKidney function declineStage renal diseaseCell proliferationInhibitor valproic acidEpithelial-stromal crosstalkKnockout mouse modelRenal cyst formationCyst burdenRenal diseaseFunction declineInterstitial fibrosisDisease progressionStromal fibrosisTargeted therapyInfantile nephronophthisisMouse modelMyofibroblast activationRenal epithelial cells
2022
Non-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 ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsHh 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
2020
Regulation and function of calcium in the cilium
Sun Z. Regulation and function of calcium in the cilium. Current Opinion In Physiology 2020, 17: 278-283. PMID: 35937971, PMCID: PMC9351618, DOI: 10.1016/j.cophys.2020.08.019.Peer-Reviewed Original Research
2019
In vivo analysis of renal epithelial cells in zebrafish
Li Y, Xu W, Jerman S, Sun Z. In vivo analysis of renal epithelial cells in zebrafish. Methods In Cell Biology 2019, 154: 163-181. PMID: 31493817, DOI: 10.1016/bs.mcb.2019.04.016.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsLeukocyte Cytoskeleton Polarization Is Initiated by Plasma Membrane Curvature from Cell Attachment
Ren C, Yuan Q, Braun M, Zhang X, Petri B, Zhang J, Kim D, Guez-Haddad J, Xue W, Pan W, Fan R, Kubes P, Sun Z, Opatowsky Y, Polleux F, Karatekin E, Tang W, Wu D. Leukocyte Cytoskeleton Polarization Is Initiated by Plasma Membrane Curvature from Cell Attachment. Developmental Cell 2019, 49: 206-219.e7. PMID: 30930167, PMCID: PMC6482112, DOI: 10.1016/j.devcel.2019.02.023.Peer-Reviewed Original ResearchCitationsAltmetricMeSH KeywordsActinsAnimalsCell AdhesionCell MembraneCell MovementCell PolarityCell-Matrix JunctionsCytoskeletonEndotheliumFemaleGTPase-Activating ProteinsHEK293 CellsHumansLeukocytesMaleMiceMice, Inbred C57BLMice, KnockoutMinor Histocompatibility AntigensMyosin Light ChainsNeutrophilsPhosphatidylinositol PhosphatesPhosphorylationPhosphotransferases (Alcohol Group Acceptor)Signal Transduction
2018
Polycystin-1 regulates bone development through an interaction with the transcriptional coactivator TAZ
Merrick D, Mistry K, Wu J, Gresko N, Baggs JE, Hogenesch JB, Sun Z, Caplan MJ. Polycystin-1 regulates bone development through an interaction with the transcriptional coactivator TAZ. Human Molecular Genetics 2018, 28: 16-30. PMID: 30215740, PMCID: PMC6298236, DOI: 10.1093/hmg/ddy322.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsMeSH KeywordsAnimalsApoptosisBone DevelopmentCell DifferentiationE1A-Associated p300 ProteinGene Expression RegulationGenes, RegulatorHEK293 CellsHumansIntracellular Signaling Peptides and ProteinsKidneyModels, AnimalMorpholinosOsteoblastsOsteogenesisPolycystic Kidney, Autosomal DominantTrans-ActivatorsTranscription FactorsTranscriptional Coactivator with PDZ-Binding Motif ProteinsTRPP Cation ChannelsZebrafishZebrafish ProteinsConceptsC-terminal tailCurly tail phenotypePolycystin-1Tail phenotypeTranscriptional coactivator TAZMessenger RNARunx2 transcriptional activityBone developmentTranscription factor Runx2Co-regulatory proteinsPkd1 mutant miceEssential coactivatorTranscriptional pathwaysTranscriptional activityOsteoblast differentiationKey mechanistic linkTAZPhysiological functionsPKD1 geneMechanistic linkRunx2MorpholinoPhenotypeMutant miceAutosomal dominant polycystic kidney disease
2017
Axonemal dynein assembly requires the R2TP complex component Pontin
Li Y, Zhao L, Yuan S, Zhang J, Sun Z. Axonemal dynein assembly requires the R2TP complex component Pontin. Development 2017, 144: 4684-4693. PMID: 29113992, PMCID: PMC5769618, DOI: 10.1242/dev.152314.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsDynein arm assemblyCilia motilityTah1-Pih1 (R2TP) complexAxonemal dynein assemblyMacromolecular protein complexesIntermediate chain 1Reptin functionsRUVBL1-RUVBL2R2TP complexAAA ATPasesCytosolic punctaArm assemblyDynein assemblyAssembly factorsCytosolic fociProtein complexesZebrafish embryosCilia defectsInner dynein armsPontinCiliated tissuesMouse testisReptinChain 1Dynein armsPalmitoylation 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 ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsPost-translational attachmentMost mammalian cellsCiliary GTPase Arl13bCilia localizationProtein palmitoylationCiliary proteinsCilia proteinsProtein localizationCilia formationMammalian cellsCilia functionPalmitoylationPrimary ciliaPlasma membraneCilia resorptionArl13bFunctional importanceMyristoylationCiliaCritical roleProteinMouse kidneyLocalizationDepalmitoylationCellsX-linked primary ciliary dyskinesia due to mutations in the cytoplasmic axonemal dynein assembly factor PIH1D3
Olcese C, Patel MP, Shoemark A, Kiviluoto S, Legendre M, Williams HJ, Vaughan CK, Hayward J, Goldenberg A, Emes RD, Munye MM, Dyer L, Cahill T, Bevillard J, Gehrig C, Guipponi M, Chantot S, Duquesnoy P, Thomas L, Jeanson L, Copin B, Tamalet A, Thauvin-Robinet C, Papon J, Garin A, Pin I, Vera G, Aurora P, Fassad MR, Jenkins L, Boustred C, Cullup T, Dixon M, Onoufriadis A, Bush A, Chung EM, Antonarakis SE, Loebinger MR, Wilson R, Armengot M, Escudier E, Hogg C, Amselem S, Sun Z, Bartoloni L, Blouin J, Mitchison H. X-linked primary ciliary dyskinesia due to mutations in the cytoplasmic axonemal dynein assembly factor PIH1D3. Nature Communications 2017, 8: 14279. PMID: 28176794, PMCID: PMC5309803, DOI: 10.1038/ncomms14279.Peer-Reviewed Original ResearchCitationsAltmetricMeSH KeywordsAdolescentAdultAnimalsApoptosis Regulatory ProteinsAxonemal DyneinsAxonemeChildChild, PreschoolCiliaCytoplasmDisease Models, AnimalExome SequencingFemaleGenes, X-LinkedGenetic Diseases, X-LinkedHEK293 CellsHSP90 Heat-Shock ProteinsHumansInfant, NewbornIntracellular Signaling Peptides and ProteinsKartagener SyndromeMaleMicroscopy, Electron, TransmissionMicrotubule ProteinsMolecular ChaperonesPedigreePhylogenyPoint MutationProtein FoldingSequence AlignmentSequence DeletionSperm MotilityZebrafish
Academic Achievements and Community Involvement
honor Young Investigator Award
UnknownChinese American Association of NephrologyDetails01/01/2007United Stateshonor John Spangler Nicholas Prize for outstanding doctoral candidate in Experimental Zoology
UnknownYale UniversityDetails01/01/1999United States
Links & Media
News
- December 08, 2020
Zhaoxia Sun Discusses the Role of Mentorship in Academia
- February 01, 2010
Bending the curve: drug halts kidney cysts
- December 01, 2009
Epilepsy Drug Shows Promise in Treating Kidney Disease, Yale Researchers Report