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Zhaoxia Sun, PhD

Associate Professor of Genetics; Co-Director of Graduate Studies, Genetics

Contact Information

Zhaoxia Sun, PhD

Mailing Address

  • PO Box 208005

    333 Cedar Street

    New Haven, CT 06520-8005

    United States

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Research Summary

We use zebrafish to study polycystic kidney disease (PKD) and other diseases caused by defects in a cell surface organelle called cilium. PKD is a common human genetic disease with severe medical consequences. Currently no directed treatment is available for this disease. Our ultimate goal is to understand cilia-mediated signaling and its role in the etiology of PKD, thus provide insight for rational designing of treatment against this disease and other ciliopathies.

Specialized Terms: Zebrafish genetics; Cilium; Kidney development; Polycystic kidney disease (PKD); Ciliopathy

Extensive Research Description

The cilium is a hair like cell surface organelle that is almost ubiquitously present on vertebrate cells. It is believed to function as an antenna for the cell to detect and transduce signals. Not surprisingly, in the past decade, there is an increasing appreciation for the vital role played by this tiny organelle in diverse developmental processes and homeostasis in vertebrates. Consistently, 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.

Using a variety of approaches in zebrafish, we are teasing 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 renal 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. Aside from kidney transplantation, no directed treatment is available for this disease. 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. We are expanding our research into the role of cilia in other diseases and are also developing novel tools for studying PKD and cilia in zebrafish.


Coauthors

Research Interests

Genetics; Kidney; Polycystic Kidney Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Zebrafish

Research Image

Cilia are widely distributed in zebrafish. Upper panel shows a zebrafish embryo stained with anti-acetylated tubulin (in green). Lower panel from left to right shows cilia (in green) in the Kupffer's vesicle, the lateral line organ, the pronephric duct, the otical vesicle and the olfactory organ.

Selected Publications

  • Cystic kidney gene seahorse regulates cilia-mediated processes and Wnt pathways.Kishimoto N, Cao Y, Park A, Sun Z. Cystic kidney gene seahorse regulates cilia-mediated processes and Wnt pathways. Developmental Cell 2008, 14: 954-61. PMID: 18539122, DOI: 10.1016/j.devcel.2008.03.010.
  • Zebrafish Tsc1 reveals functional interactions between the cilium and the TOR pathway.DiBella LM, Park A, Sun Z. Zebrafish Tsc1 reveals functional interactions between the cilium and the TOR pathway. Human Molecular Genetics 2009, 18: 595-606. PMID: 19008302, PMCID: PMC2722215, DOI: 10.1093/hmg/ddn384.
  • Cilia localization is essential for in vivo functions of the Joubert syndrome protein Arl13b/Scorpion.Duldulao NA, Lee S, Sun Z. Cilia localization is essential for in vivo functions of the Joubert syndrome protein Arl13b/Scorpion. Development (Cambridge, England) 2009, 136: 4033-42. PMID: 19906870, PMCID: PMC2778746, DOI: 10.1242/dev.036350.
  • Chemical modifier screen identifies HDAC inhibitors as suppressors of PKD models.Cao 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: 21819-24. PMID: 19966229, PMCID: PMC2799791, DOI: 10.1073/pnas.0911987106.
  • The zebrafish foxj1a transcription factor regulates cilia function in response to injury and epithelial stretch.Hellman 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: 18499-504. PMID: 20937855, PMCID: PMC2972951, DOI: 10.1073/pnas.1005998107.
  • Intraflagellar transport proteins are essential for cilia formation and for planar cell polarity.Cao 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 : JASN 2010, 21: 1326-33. PMID: 20576807, PMCID: PMC2938599, DOI: 10.1681/ASN.2009091001.
  • Qilin is essential for cilia assembly and normal kidney development in zebrafish.Li 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 flow.Engel BD, Ishikawa H, Feldman JL, Wilson CW, Chuang PT, 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 (Hoboken, N.J.) 2011, 68: 188-203. PMID: 21360831, DOI: 10.1002/cm.20504.
  • Target-of-rapamycin complex 1 (Torc1) signaling modulates cilia size and function through protein synthesis regulation.Yuan 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: 2021-6. 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 mechanism.Merrick 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 2012, 22: 197-210. PMID: 22178500, PMCID: PMC3264829, DOI: 10.1016/j.devcel.2011.10.028.
  • Reptin/Ruvbl2 is a Lrrc6/Seahorse interactor essential for cilia motility.Zhao 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: 12697-702. PMID: 23858445, PMCID: PMC3732945, DOI: 10.1073/pnas.1300968110.
  • IFT27, encoding a small GTPase component of IFT particles, is mutated in a consanguineous family with Bardet-Biedl syndrome.Aldahmesh MA, Li Y, Alhashem A, Anazi S, Alkuraya H, Hashem M, Awaji AA, Sogaty S, Alkharashi A, Alzahrani S, Al Hazzaa SA, 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: 3307-15. PMID: 24488770, PMCID: PMC4047285, DOI: 10.1093/hmg/ddu044.
  • Intraciliary calcium oscillations initiate vertebrate left-right asymmetry.Yuan S, Zhao L, Brueckner M, Sun Z. Intraciliary calcium oscillations initiate vertebrate left-right asymmetry. Current Biology : CB 2015, 25: 556-67. PMID: 25660539, PMCID: PMC4469357, DOI: 10.1016/j.cub.2014.12.051.
  • Endothelial cilia are essential for developmental vascular integrity in zebrafish.Kallakuri 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 : JASN 2015, 26: 864-75. PMID: 25214579, PMCID: PMC4378100, DOI: 10.1681/ASN.2013121314.
  • Deletion of ADP Ribosylation Factor-Like GTPase 13B Leads to Kidney Cysts.Li 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 : JASN 2016, 27: 3628-3638. PMID: 27153923, PMCID: PMC5118478, DOI: 10.1681/ASN.2015091004.
  • Hypomorphic mutations identified in the candidate Leber congenital amaurosis gene CLUAP1.Soens 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 : Official Journal Of The American College Of Medical Genetics 2016, 18: 1044-51. PMID: 26820066, PMCID: PMC4965339, DOI: 10.1038/gim.2015.205.
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