Zhaoxia Sun, PhD
Research & Publications
Biography
News
Research Summary
We study a tiny cell surface organelle called the cilium. The cilium plays a critical role in animal development and in multiple human diseases. We are particularly interested in two genetics diseases caused by ciliary defects: polycystic kidney disease (PKD) and primary ciliary dyskinesia (PCD). Our ultimate goal is to understand how cilia are built and how cilia mediate cellular function, thus provide insight for rational designing of treatment against ciliopathies, diseases caused by ciliary defects.
Specialized Terms: Cilium; Ciliopathy; Kidney Development; Mouse Genetics; Primary ciliary dyskinesia (PCD); Polycystic Kidney Disease (PKD); Zebrafish Genetics
Extensive Research Description
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.
Coauthors
Research Interests
Fibrosis; Genetics; Kartagener Syndrome; Kidney; Polycystic Kidney Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Zebrafish; Ciliopathies
Selected Publications
- Inactivation of Invs/Nphp2 in renal epithelial cells drives infantile nephronophthisis like phenotypes in mouseLi 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.
- 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.
- Regulation and function of calcium in the ciliumSun 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.
- In vivo analysis of renal epithelial cells in zebrafishLi Y, Xu W, Jerman S, Sun Z. In vivo analysis of renal epithelial cells in zebrafish. 2019, 154: 163-181. PMID: 31493817, DOI: 10.1016/bs.mcb.2019.04.016.
- Leukocyte Cytoskeleton Polarization Is Initiated by Plasma Membrane Curvature from Cell AttachmentRen 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.
- Polycystin-1 regulates bone development through an interaction with the transcriptional coactivator TAZMerrick 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.
- Palmitoylation of the ciliary GTPase ARL13b is necessary for its stability and its role in cilia formationRoy 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.
- X-linked primary ciliary dyskinesia due to mutations in the cytoplasmic axonemal dynein assembly factor PIH1D3Olcese 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.
- Chapter Two Using Zebrafish to Study Kidney Development and DiseaseJerman S, Sun Z. Chapter Two Using Zebrafish to Study Kidney Development and Disease. 2017, 124: 41-79. PMID: 28335864, DOI: 10.1016/bs.ctdb.2016.11.008.
- Axonemal dynein assembly requires the R2TP complex component PontinLi 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.
- Deletion of ADP Ribosylation Factor-Like GTPase 13B Leads to Kidney CystsLi Y, Tian X, Ma M, Jerman S, Kong S, Somlo S, Sun Z. Deletion of ADP Ribosylation Factor-Like GTPase 13B Leads to Kidney Cysts. Journal Of The American Society Of Nephrology 2016, 27: 3628-3638. PMID: 27153923, PMCID: PMC5118478, DOI: 10.1681/asn.2015091004.
- Hypomorphic mutations identified in the candidate Leber congenital amaurosis gene CLUAP1Soens ZT, Li Y, Zhao L, Eblimit A, Dharmat R, Li Y, Chen Y, Naqeeb M, Fajardo N, Lopez I, Sun Z, Koenekoop RK, Chen R. Hypomorphic mutations identified in the candidate Leber congenital amaurosis gene CLUAP1. Genetics In Medicine 2016, 18: 1044-1051. PMID: 26820066, PMCID: PMC4965339, DOI: 10.1038/gim.2015.205.
- Intraciliary Calcium Oscillations Initiate Vertebrate Left-Right AsymmetryYuan S, Zhao L, Brueckner M, Sun Z. Intraciliary Calcium Oscillations Initiate Vertebrate Left-Right Asymmetry. Current Biology 2015, 25: 556-567. PMID: 25660539, PMCID: PMC4469357, DOI: 10.1016/j.cub.2014.12.051.
- Endothelial Cilia Are Essential for Developmental Vascular Integrity in ZebrafishKallakuri S, Yu JA, Li J, Li Y, Weinstein BM, Nicoli S, Sun Z. Endothelial Cilia Are Essential for Developmental Vascular Integrity in Zebrafish. Journal Of The American Society Of Nephrology 2014, 26: 864-875. PMID: 25214579, PMCID: PMC4378100, DOI: 10.1681/asn.2013121314.
- IFT27, encoding a small GTPase component of IFT particles, is mutated in a consanguineous family with Bardet–Biedl syndromeAldahmesh MA, Li Y, Alhashem A, Anazi S, Alkuraya H, Hashem M, Awaji AA, Sogaty S, Alkharashi A, Alzahrani S, Hazzaa S, Xiong Y, Kong S, Sun Z, Alkuraya FS. IFT27, encoding a small GTPase component of IFT particles, is mutated in a consanguineous family with Bardet–Biedl syndrome. Human Molecular Genetics 2014, 23: 3307-3315. PMID: 24488770, PMCID: PMC4047285, DOI: 10.1093/hmg/ddu044.
- Expanding Horizons: Ciliary Proteins Reach Beyond CiliaYuan S, Sun Z. Expanding Horizons: Ciliary Proteins Reach Beyond Cilia. Annual Review Of Genetics 2013, 47: 353-376. PMID: 24016188, PMCID: PMC5703194, DOI: 10.1146/annurev-genet-111212-133243.
- ZMYND10 Is Mutated in Primary Ciliary Dyskinesia and Interacts with LRRC6Zariwala MA, Gee HY, Kurkowiak M, Al-Mutairi DA, Leigh MW, Hurd TW, Hjeij R, Dell SD, Chaki M, Dougherty GW, Adan M, Spear PC, Esteve-Rudd J, Loges NT, Rosenfeld M, Diaz KA, Olbrich H, Wolf WE, Sheridan E, Batten TF, Halbritter J, Porath JD, Kohl S, Lovric S, Hwang DY, Pittman JE, Burns KA, Ferkol TW, Sagel SD, Olivier KN, Morgan LC, Werner C, Raidt J, Pennekamp P, Sun Z, Zhou W, Airik R, Natarajan S, Allen SJ, Amirav I, Wieczorek D, Landwehr K, Nielsen K, Schwerk N, Sertic J, Köhler G, Washburn J, Levy S, Fan S, Koerner-Rettberg C, Amselem S, Williams DS, Mitchell BJ, Drummond IA, Otto EA, Omran H, Knowles MR, Hildebrandt F. ZMYND10 Is Mutated in Primary Ciliary Dyskinesia and Interacts with LRRC6. American Journal Of Human Genetics 2013, 93: 336-345. PMID: 23891469, PMCID: PMC3738827, DOI: 10.1016/j.ajhg.2013.06.007.
- Reptin/Ruvbl2 is a Lrrc6/Seahorse interactor essential for cilia motilityZhao L, Yuan S, Cao Y, Kallakuri S, Li Y, Kishimoto N, DiBella L, Sun Z. Reptin/Ruvbl2 is a Lrrc6/Seahorse interactor essential for cilia motility. Proceedings Of The National Academy Of Sciences Of The United States Of America 2013, 110: 12697-12702. PMID: 23858445, PMCID: PMC3732945, DOI: 10.1073/pnas.1300968110.
- Polycystin-2 mutations lead to impaired calcium cycling in the heart and predispose to dilated cardiomyopathyPaavola J, Schliffke S, Rossetti S, Kuo I, Yuan S, Sun Z, Harris PC, Torres VE, Ehrlich BE. Polycystin-2 mutations lead to impaired calcium cycling in the heart and predispose to dilated cardiomyopathy. Journal Of Molecular And Cellular Cardiology 2013, 58: 199-208. PMID: 23376035, PMCID: PMC3636149, DOI: 10.1016/j.yjmcc.2013.01.015.
- Chapter Nine Dissecting the Functional Interplay Between the TOR Pathway and the Cilium in ZebrafishYuan S, Zhao L, Sun Z. Chapter Nine Dissecting the Functional Interplay Between the TOR Pathway and the Cilium in Zebrafish. 2013, 525: 159-189. PMID: 23522470, DOI: 10.1016/b978-0-12-397944-5.00009-2.
- TORC1-mediated protein synthesis regulates cilia size and functionYuan S, Sun Z. TORC1-mediated protein synthesis regulates cilia size and function. Cell Cycle 2012, 11: 1750-1752. PMID: 22517434, PMCID: PMC3372384, DOI: 10.4161/cc.20312.
- Target-of-rapamycin complex 1 (Torc1) signaling modulates cilia size and function through protein synthesis regulationYuan S, Li J, Diener DR, Choma MA, Rosenbaum JL, Sun Z. Target-of-rapamycin complex 1 (Torc1) signaling modulates cilia size and function through protein synthesis regulation. Proceedings Of The National Academy Of Sciences Of The United States Of America 2012, 109: 2021-2026. PMID: 22308353, PMCID: PMC3277533, DOI: 10.1073/pnas.1112834109.
- The γ-Secretase Cleavage Product of Polycystin-1 Regulates TCF and CHOP-Mediated Transcriptional Activation through a p300-Dependent MechanismMerrick D, Chapin H, Baggs JE, Yu Z, Somlo S, Sun Z, Hogenesch JB, Caplan MJ. The γ-Secretase Cleavage Product of Polycystin-1 Regulates TCF and CHOP-Mediated Transcriptional Activation through a p300-Dependent Mechanism. Developmental Cell 2011, 22: 197-210. PMID: 22178500, PMCID: PMC3264829, DOI: 10.1016/j.devcel.2011.10.028.
- Qilin Is Essential for Cilia Assembly and Normal Kidney Development in ZebrafishLi J, Sun Z. Qilin Is Essential for Cilia Assembly and Normal Kidney Development in Zebrafish. PLOS ONE 2011, 6: e27365. PMID: 22102889, PMCID: PMC3216947, DOI: 10.1371/journal.pone.0027365.
- A cell‐based screen for inhibitors of flagella‐driven motility in Chlamydomonas reveals a novel modulator of ciliary length and retrograde actin flowEngel BD, Ishikawa H, Feldman JL, Wilson CW, Chuang P, Snedecor J, Williams J, Sun Z, Marshall WF. A cell‐based screen for inhibitors of flagella‐driven motility in Chlamydomonas reveals a novel modulator of ciliary length and retrograde actin flow. Cytoskeleton 2011, 68: 188-203. PMID: 21360831, DOI: 10.1002/cm.20504.
- Chapter 3 Analysis of Cilia Structure and Function in ZebrafishMalicki J, Avanesov A, Li J, Yuan S, Sun Z. Chapter 3 Analysis of Cilia Structure and Function in Zebrafish. 2011, 101: 39-74. PMID: 21550439, DOI: 10.1016/b978-0-12-387036-0.00003-7.
- The zebrafish foxj1a transcription factor regulates cilia function in response to injury and epithelial stretchHellman NE, Liu Y, Merkel E, Austin C, Le Corre S, Beier DR, Sun Z, Sharma N, Yoder BK, Drummond IA. The zebrafish foxj1a transcription factor regulates cilia function in response to injury and epithelial stretch. Proceedings Of The National Academy Of Sciences Of The United States Of America 2010, 107: 18499-18504. PMID: 20937855, PMCID: PMC2972951, DOI: 10.1073/pnas.1005998107.
- Cilia in cell signaling and human disordersDuldulao NA, Li J, Sun Z. Cilia in cell signaling and human disorders. Protein & Cell 2010, 1: 726-736. PMID: 21203914, PMCID: PMC4875200, DOI: 10.1007/s13238-010-0098-7.
- Intraflagellar Transport Proteins Are Essential for Cilia Formation and for Planar Cell PolarityCao Y, Park A, Sun Z. Intraflagellar Transport Proteins Are Essential for Cilia Formation and for Planar Cell Polarity. Journal Of The American Society Of Nephrology 2010, 21: 1326-1333. PMID: 20576807, PMCID: PMC2938599, DOI: 10.1681/asn.2009091001.
- Chemical modifier screen identifies HDAC inhibitors as suppressors of PKD modelsCao Y, Semanchik N, Lee SH, Somlo S, Barbano PE, Coifman R, Sun Z. Chemical modifier screen identifies HDAC inhibitors as suppressors of PKD models. Proceedings Of The National Academy Of Sciences Of The United States Of America 2009, 106: 21819-21824. PMID: 19966229, PMCID: PMC2799791, DOI: 10.1073/pnas.0911987106.
- Cilia localization is essential for in vivo functions of the Joubert syndrome protein Arl13b/ScorpionDuldulao NA, Lee S, Sun Z. Cilia localization is essential for in vivo functions of the Joubert syndrome protein Arl13b/Scorpion. Development 2009, 136: 4033-4042. PMID: 19906870, PMCID: PMC2778746, DOI: 10.1242/dev.036350.
- Microinjection of mRNA and morpholino antisense oligonucleotides in zebrafish embryos.Yuan S, Sun Z. Microinjection of mRNA and morpholino antisense oligonucleotides in zebrafish embryos. Journal Of Visualized Experiments 2009 PMID: 19488022, PMCID: PMC2762915, DOI: 10.3791/1113.
- Zebrafish Tsc1 reveals functional interactions between the cilium and the TOR pathwayDiBella LM, Park A, Sun Z. Zebrafish Tsc1 reveals functional interactions between the cilium and the TOR pathway. Human Molecular Genetics 2008, 18: 595-606. PMID: 19008302, PMCID: PMC2722215, DOI: 10.1093/hmg/ddn384.
- Cystic Kidney Gene seahorse Regulates Cilia-Mediated Processes and Wnt PathwaysKishimoto N, Cao Y, Park A, Sun Z. Cystic Kidney Gene seahorse Regulates Cilia-Mediated Processes and Wnt Pathways. Developmental Cell 2008, 14: 954-961. PMID: 18539122, DOI: 10.1016/j.devcel.2008.03.010.
- Identification of 315 genes essential for early zebrafish development.Amsterdam A, Nissen RM, Sun Z, Swindell EC, Farrington S, Hopkins N. Identification of 315 genes essential for early zebrafish development. Proceedings Of The National Academy Of Sciences Of The United States Of America 2004, 101: 12792-7. PMID: 15256591, PMCID: PMC516474, DOI: 10.1073/pnas.0403929101.
- A genetic screen in zebrafish identifies cilia genes as a principal cause of cystic kidney.Sun Z, Amsterdam A, Pazour GJ, Cole DG, Miller MS, Hopkins N. A genetic screen in zebrafish identifies cilia genes as a principal cause of cystic kidney. Development (Cambridge, England) 2004, 131: 4085-93. PMID: 15269167, DOI: 10.1242/dev.01240.
- Insertional mutagenesis in zebrafish rapidly identifies genes essential for early vertebrate development.Golling G, Amsterdam A, Sun Z, Antonelli M, Maldonado E, Chen W, Burgess S, Haldi M, Artzt K, Farrington S, Lin SY, Nissen RM, Hopkins N. Insertional mutagenesis in zebrafish rapidly identifies genes essential for early vertebrate development. Nature Genetics 2002, 31: 135-40. PMID: 12006978, DOI: 10.1038/ng896.
- Rad9 Phosphorylation Sites Couple Rad53 to the Saccharomyces cerevisiae DNA Damage CheckpointSchwartz MF, Duong JK, Sun Z, Morrow JS, Pradhan D, Stern DF. Rad9 Phosphorylation Sites Couple Rad53 to the Saccharomyces cerevisiae DNA Damage Checkpoint. Molecular Cell 2002, 9: 1055-1065. PMID: 12049741, DOI: 10.1016/s1097-2765(02)00532-4.
- vhnf1, the MODY5 and familial GCKD-associated gene, regulates regional specification of the zebrafish gut, pronephros, and hindbrain.Sun Z, Hopkins N. vhnf1, the MODY5 and familial GCKD-associated gene, regulates regional specification of the zebrafish gut, pronephros, and hindbrain. Genes & Development 2001, 15: 3217-29. PMID: 11731484, PMCID: PMC312837, DOI: 10.1101/gad946701.
- A large-scale insertional mutagenesis screen in zebrafish.Amsterdam A, Burgess S, Golling G, Chen W, Sun Z, Townsend K, Farrington S, Haldi M, Hopkins N. A large-scale insertional mutagenesis screen in zebrafish. Genes & Development 1999, 13: 2713-24. PMID: 10541557, PMCID: PMC317115, DOI: 10.1101/gad.13.20.2713.
- Mutations in SPK1/RAD53 that specifically abolish checkpoint but not growth-related functionsFay DS, Sun Z, Stern D. Mutations in SPK1/RAD53 that specifically abolish checkpoint but not growth-related functions. Current Genetics 1997, 31: 97-105. PMID: 9021124, DOI: 10.1007/s002940050181.
- Spk1/Rad53 is regulated by Mec1-dependent protein phosphorylation in DNA replication and damage checkpoint pathways.Sun Z, Fay DS, Marini F, Foiani M, Stern DF. Spk1/Rad53 is regulated by Mec1-dependent protein phosphorylation in DNA replication and damage checkpoint pathways. Genes & Development 1996, 10: 395-406. PMID: 8600024, DOI: 10.1101/gad.10.4.395.