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    Gregory J Pazour PhD

    TitleProfessor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentProgram in Molecular Medicine
    AddressUniversity of Massachusetts Medical School
    373 Plantation Street
    Worcester MA 01605
    Phone508-856-8078
      Other Positions
      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentCell Biology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentInterdisciplinary Graduate Program

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentMD/PhD Program

      InstitutionUMMS - Programs, Centers and Institutes
      DepartmentProgram in Cell Dynamics

        Overview 
        Narrative

        Academic Background

        Ph.D., 1991, University of Minnesota

        Function of the Mammalian Primary Cilium and Mechanisms of Eukaryotic Ciliary Assembly

        We are interested in the function of primary cilia. These organelles play vital roles in the development of mammals and in the etiology of diseases such as polycystic kidney disease and blindness. Our work combines in vitro cell culture studies with mutant mouse models to understand the role of cilia in controlling kidney architecture and the formation of the photoreceptor outer segment.

        In the kidney, the epithelial cells lining the ducts and tubules of the nephron have prominent primary cilia extending from their surface into the lumen of the duct. We showed that the Tg737 mouse model of polycystic kidney disease has defects in these cilia. The gene mutated in the Tg737 mouse encodes the IFT88 subunit of the intraflagellar transport (IFT) particle. IFT is bidirectional movement along the length of cilia that is thought to carry materials needed for assembly and maintenance of cilia and flagella.

        Figure 1. Tg737 Scanning EM

        It is thought that primary cilia on kidney epithelial and other cells are sensory organelles that monitor the extracellular environment.Information perceived by cilia control aspects of cell physiology including proliferation and differentiation, along with cellular and organ architecture. We are currently focused on understanding how cilia function to maintain the normal architecture of the kidney and prevent cystic disease. To do this we have created a floxed allele of the gene encoding the IFT20 subunit of the IFT particle. Deletion of this gene in the kidney causes severe polycystic kidney disease. During the development of cystic disease in this animal, the collection ducts (labeled green in Figure 2) greatly enlarge and disrupt the architecture of the kidney.

        Figure 2. IFT20 Deletion Histology

        Another focus of the laboratory is to understand how the outer segments of vertebrate photoreceptor rod and cone cells are assembled.These structures are highly modified cilia and require intraflagellar transport for assembly. Defects in transport cause progressive retinal degeneration eventually leading to blindness. To study the role of intraflagellar transport in photoreceptor outer segment assembly, we deleted IFT20 specifically in cone cells. This initially causes photopigments to accumulate in the cell body and causes cone cell degeneration, eventually destroying all the cones. Rod cells are not affected in these animals. In Figure 3 cone outer segments are labeled green, rod outer segments are labeled red, and photoreceptor nuclei are labeled blue.

        Figure 3. IFT20 Retina



        Rotation Projects

        Potential Rotation Projects

        Rotation projects in my laboratory will involve questions of how cilia are assembled and the function these organelles play in mammals.

        Projects vary depending on ongoing work in the laboratory and interests of the rotation student. Rotations in my laboratory can give students exposure to a range of techniques from mouse breeding and histological analysis of mouse tissues to mammalian cell culture and other cell biological techniques.



        Bibliographic 
        selected publications
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        1. Ma M, Tian X, Igarashi P, Pazour GJ, Somlo S. Loss of cilia suppresses cyst growth in genetic models of autosomal dominant polycystic kidney disease. Nat Genet. 2013 Aug 28; 45(9):1004-12.
          View in: PubMed
        2. Schmidts M, Frank V, Eisenberger T, Al Turki S, Bizet AA, Antony D, Rix S, Decker C, Bachmann N, Bald M, Vinke T, Toenshoff B, Di Donato N, Neuhann T, Hartley JL, Maher ER, Bogdanovic R, Peco-Antic A, Mache C, Hurles ME, Joksic I, Guc-Šcekic M, Dobricic J, Brankovic-Magic M. Combined NGS Approaches Identify Mutations in the Intraflagellar Transport Gene IFT140 in Skeletal Ciliopathies with Early Progressive Kidney Disease. Hum Mutat. 2013 May; 34(5):714-24.
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        3. Follit JA, Pazour GJ. Analysis of Ciliary Membrane Protein Dynamics Using SNAP Technology. Methods Enzymol. 2013; 524:195-204.
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        4. Gu W, Lee HC, Chaves D, Youngman EM, Pazour GJ, Conte D, Mello CC. CapSeq and CIP-TAP Identify Pol II Start Sites and Reveal Capped Small RNAs as C. elegans piRNA Precursors. Cell. 2012 Dec 21; 151(7):1488-500.
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        5. Engel BD, Ishikawa H, Wemmer KA, Geimer S, Wakabayashi K, Hirono M, Craige B, Pazour GJ, Witman GB, Kamiya R, Marshall WF. The role of retrograde intraflagellar transport in flagellar assembly, maintenance, and function. J Cell Biol. 2012 Oct 1; 199(1):151-67.
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        6. Keady BT, Samtani R, Tobita K, Tsuchya M, San Agustin JT, Follit JA, Jonassen JA, Subramanian R, Lo CW, Pazour GJ. IFT25 Links the Signal-Dependent Movement of Hedgehog Components to Intraflagellar Transport. Dev Cell. 2012 May 15; 22(5):940-51.
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        7. Jonassen JA, Sanagustin J, Baker SP, Pazour GJ. Disruption of IFT Complex A Causes Cystic Kidneys without Mitotic Spindle Misorientation. J Am Soc Nephrol. 2012 Jan 26.
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        8. Hom EF, Witman GB, Harris EH, Dutcher SK, Kamiya R, Mitchell DR, Pazour GJ, Porter ME, Sale WS, Wirschell M, Yagi T, King SM. A unified taxonomy for ciliary dyneins. Cytoskeleton (Hoboken). 2011 Oct; 68(10):555-65.
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        9. Amador-Arjona A, Elliott J, Miller A, Ginbey A, Pazour GJ, Enikolopov G, Roberts AJ, Terskikh AV. Primary cilia regulate proliferation of amplifying progenitors in adult hippocampus: implications for learning and memory. J Neurosci. 2011 Jul 6; 31(27):9933-44.
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        10. Keady BT, Le YZ, Pazour GJ. IFT20 is required for opsin trafficking and photoreceptor outer segment development. Mol Biol Cell. 2011 Apr; 22(7):921-30.
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        11. Cui C, Chatterjee B, Francis D, Yu Q, Sanagustin JT, Francis R, Tansey T, Henry C, Wang B, Lemley B, Pazour GJ, Lo CW. Disruption of Mks1 localization to the mother centriole causes cilia defects and developmental malformations in Meckel-Gruber syndrome. Dis Model Mech. 2011 Jan-Feb; 4(1):43-56.
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        12. McDermott KM, Liu BY, Tlsty TD, Pazour GJ. Primary Cilia Regulate Branching Morphogenesis during Mammary Gland Development. Curr Biol. 2010 Apr 27; 20(8):731-7.
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        13. Follit JA, Li L, Vucica Y, Pazour GJ. The cytoplasmic tail of fibrocystin contains a ciliary targeting sequence. J Cell Biol. 2010 Jan 11; 188(1):21-8.
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        14. Lechtreck KF, Johnson EC, Sakai T, Cochran D, Ballif BA, Rush J, Pazour GJ, Ikebe M, Witman GB. The Chlamydomonas reinhardtii BBSome is an IFT cargo required for export of specific signaling proteins from flagella. J Cell Biol. 2009 Dec 28; 187(7):1117-32.
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        15. Pazour GJ. Immunoprecipitation to examine protein complexes. Methods Cell Biol. 2009; 91:135-42.
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        16. SanAgustin JT, Follit JA, Hendricks G, Pazour GJ. Scanning electron microscopy to examine cells and organs. Methods Cell Biol. 2009; 91:81-7.
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        17. Finetti F, Paccani SR, Riparbelli MG, Giacomello E, Perinetti G, Pazour GJ, Rosenbaum JL, Baldari CT. Intraflagellar transport is required for polarized recycling of the TCR/CD3 complex to the immune synapse. Nat Cell Biol. 2009 Nov; 11(11):1332-9.
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        18. Clement CA, Kristensen SG, Møllgård K, Pazour GJ, Yoder BK, Larsen LA, Christensen ST. The primary cilium coordinates early cardiogenesis and hedgehog signaling in cardiomyocyte differentiation. J Cell Sci. 2009 Sep 1; 122(Pt 17):3070-82.
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        19. Follit JA, Xu F, Keady BT, Pazour GJ. Characterization of mouse IFT complex B. Cell Motil Cytoskeleton. 2009 Aug; 66(8):457-68.
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        20. Follit JA, San Agustin JT, Xu F, Jonassen JA, Samtani R, Lo CW, Pazour GJ. The Golgin GMAP210/TRIP11 anchors IFT20 to the Golgi complex. PLoS Genet. 2008 Dec; 4(12):e1000315.
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        21. Jonassen JA, San Agustin J, Follit JA, Pazour GJ. Deletion of IFT20 in the mouse kidney causes misorientation of the mitotic spindle and cystic kidney disease. J Cell Biol. 2008 Nov 3; 183(3):377-84.
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        22. Tanner CA, Rompolas P, Patel-King RS, Gorbatyuk O, Wakabayashi K, Pazour GJ, King SM. Three members of the LC8/DYNLL family are required for outer arm dynein motor function. Mol Biol Cell. 2008 Sep; 19(9):3724-34.
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        23. Pazour GJ, Bloodgood RA. Targeting proteins to the ciliary membrane. Curr Top Dev Biol. 2008; 85:115-49.
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        24. Huang K, Diener DR, Mitchell A, Pazour GJ, Witman GB, Rosenbaum JL. Function and dynamics of PKD2 in Chlamydomonas reinhardtii flagella. J Cell Biol. 2007 Nov 5; 179(3):501-14.
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        25. Merchant SS, Prochnik SE, Vallon O, Harris EH, Karpowicz SJ, Witman GB, Terry A, Salamov A, Fritz-Laylin LK, Maréchal-Drouard L, Marshall WF, Qu LH, Nelson DR, Sanderfoot AA, Spalding MH, Kapitonov VV, Ren Q, Ferris P, Lindquist E, Shapiro H, Lucas SM, Grimwood J, Schmutz J, Cardol P, Cerutti H, Chanfreau G, Chen CL, Cognat V, Croft MT, Dent R, Dutcher S, Fernández E, Fukuzawa H, González-Ballester D, González-Halphen D, Hallmann A, Hanikenne M, Hippler M, Inwood W, Jabbari K, Kalanon M, Kuras R, Lefebvre PA, Lemaire SD, Lobanov AV, Lohr M, Manuell A, Meier I, Mets L, Mittag M, Mittelmeier T, Moroney JV, Moseley J, Napoli C, Nedelcu AM, Niyogi K, Novoselov SV, Paulsen IT, Pazour G, Purton S, Ral JP, Riaño-Pachón DM, Riekhof W, Rymarquis L, Schroda M, Stern D, Umen J, Willows R, Wilson N, Zimmer SL, Allmer J, Balk J, Bisova K, Chen CJ, Elias M, Gendler K, Hauser C, Lamb MR, Ledford H, Long JC, Minagawa J, Page MD, Pan J, Pootakham W, Roje S, Rose A, Stahlberg E, Terauchi AM, Yang P, Ball S, Bowler C, Dieckmann CL, Gladyshev VN, Green P, Jorgensen R, Mayfield S, Mueller-Roeber B, Rajamani S, Sayre RT, Brokstein P, Dubchak I, Goodstein D, Hornick L, Huang YW, Jhaveri J, Luo Y, Martínez D, Ngau WC, Otillar B, Poliakov A, Porter A, Szajkowski L, Werner G, Zhou K, Grigoriev IV, Rokhsar DS, Grossman AR. The Chlamydomonas genome reveals the evolution of key animal and plant functions. Science. 2007 Oct 12; 318(5848):245-50.
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        26. Luby-Phelps K, Fogerty J, Baker SA, Pazour GJ, Besharse JC. Spatial distribution of intraflagellar transport proteins in vertebrate photoreceptors. Vision Res. 2008 Feb; 48(3):413-23.
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        27. Palenik B, Grimwood J, Aerts A, Rouzé P, Salamov A, Putnam N, Dupont C, Jorgensen R, Derelle E, Rombauts S, Zhou K, Otillar R, Merchant SS, Podell S, Gaasterland T, Napoli C, Gendler K, Manuell A, Tai V, Vallon O, Piganeau G, Jancek S, Heijde M, Jabbari K, Bowler C, Lohr M, Robbens S, Werner G, Dubchak I, Pazour GJ, Ren Q, Paulsen I, Delwiche C, Schmutz J, Rokhsar D, Van de Peer Y, Moreau H, Grigoriev IV. The tiny eukaryote Ostreococcus provides genomic insights into the paradox of plankton speciation. Proc Natl Acad Sci U S A. 2007 May 1; 104(18):7705-10.
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        28. Hou Y, Qin H, Follit JA, Pazour GJ, Rosenbaum JL, Witman GB. Functional analysis of an individual IFT protein: IFT46 is required for transport of outer dynein arms into flagella. J Cell Biol. 2007 Feb 26; 176(5):653-65.
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        29. Fliegauf M, Horvath J, von Schnakenburg C, Olbrich H, Müller D, Thumfart J, Schermer B, Pazour GJ, Neumann HP, Zentgraf H, Benzing T, Omran H. Nephrocystin specifically localizes to the transition zone of renal and respiratory cilia and photoreceptor connecting cilia. J Am Soc Nephrol. 2006 Sep; 17(9):2424-33.
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        30. Gunay-Aygun M, Avner ED, Bacallao RL, Choyke PL, Flynn JT, Germino GG, Guay-Woodford L, Harris P, Heller T, Ingelfinger J, Kaskel F, Kleta R, LaRusso NF, Mohan P, Pazour GJ, Shneider BL, Torres VE, Wilson P, Zak C, Zhou J, Gahl WA. Autosomal recessive polycystic kidney disease and congenital hepatic fibrosis: summary statement of a first National Institutes of Health/Office of Rare Diseases conference. J Pediatr. 2006 Aug; 149(2):159-64.
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        31. Follit JA, Tuft RA, Fogarty KE, Pazour GJ. The intraflagellar transport protein IFT20 is associated with the Golgi complex and is required for cilia assembly. Mol Biol Cell. 2006 Sep; 17(9):3781-92.
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        32. Yang P, Diener DR, Yang C, Kohno T, Pazour GJ, Dienes JM, Agrin NS, King SM, Sale WS, Kamiya R, Rosenbaum JL, Witman GB. Radial spoke proteins of Chlamydomonas flagella. J Cell Sci. 2006 Mar 15; 119(Pt 6):1165-74.
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        33. Schneider L, Clement CA, Teilmann SC, Pazour GJ, Hoffmann EK, Satir P, Christensen ST. PDGFRalphaalpha signaling is regulated through the primary cilium in fibroblasts. Curr Biol. 2005 Oct 25; 15(20):1861-6.
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        34. DiBella LM, Gorbatyuk O, Sakato M, Wakabayashi K, Patel-King RS, Pazour GJ, Witman GB, King SM. Differential light chain assembly influences outer arm dynein motor function. Mol Biol Cell. 2005 Dec; 16(12):5661-74.
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        35. Teilmann SC, Byskov AG, Pedersen PA, Wheatley DN, Pazour GJ, Christensen ST. Localization of transient receptor potential ion channels in primary and motile cilia of the female murine reproductive organs. Mol Reprod Dev. 2005 Aug; 71(4):444-52.
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        36. Pazour GJ, Agrin N, Leszyk J, Witman GB. Proteomic analysis of a eukaryotic cilium. J Cell Biol. 2005 Jul 4; 170(1):103-13.
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        37. Pazour GJ, Agrin N, Walker BL, Witman GB. Identification of predicted human outer dynein arm genes: candidates for primary ciliary dyskinesia genes. J Med Genet. 2006 Jan; 43(1):62-73.
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        38. Armbrust EV, Berges JA, Bowler C, Green BR, Martinez D, Putnam NH, Zhou S, Allen AE, Apt KE, Bechner M, Brzezinski MA, Chaal BK, Chiovitti A, Davis AK, Demarest MS, Detter JC, Glavina T, Goodstein D, Hadi MZ, Hellsten U, Hildebrand M, Jenkins BD, Jurka J, Kapitonov VV, Kröger N, Lau WW, Lane TW, Larimer FW, Lippmeier JC, Lucas S, Medina M, Montsant A, Obornik M, Parker MS, Palenik B, Pazour GJ, Richardson PM, Rynearson TA, Saito MA, Schwartz DC, Thamatrakoln K, Valentin K, Vardi A, Wilkerson FP, Rokhsar DS. The genome of the diatom Thalassiosira pseudonana: ecology, evolution, and metabolism. Science. 2004 Oct 1; 306(5693):79-86.
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        39. Pazour GJ. Intraflagellar transport and cilia-dependent renal disease: the ciliary hypothesis of polycystic kidney disease. J Am Soc Nephrol. 2004 Oct; 15(10):2528-36.
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        40. Jurczyk A, Gromley A, Redick S, San Agustin J, Witman G, Pazour GJ, Peters DJ, Doxsey S. Pericentrin forms a complex with intraflagellar transport proteins and polycystin-2 and is required for primary cilia assembly. J Cell Biol. 2004 Aug 30; 166(5):637-43.
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        41. DiBella LM, Sakato M, Patel-King RS, Pazour GJ, King SM. The LC7 light chains of Chlamydomonas flagellar dyneins interact with components required for both motor assembly and regulation. Mol Biol Cell. 2004 Oct; 15(10):4633-46.
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        42. Pazour GJ. Comparative genomics: prediction of the ciliary and basal body proteome. Curr Biol. 2004 Jul 27; 14(14):R575-7.
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        43. 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. 2004 Aug; 131(16):4085-93.
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        44. Hou Y, Pazour GJ, Witman GB. A dynein light intermediate chain, D1bLIC, is required for retrograde intraflagellar transport. Mol Biol Cell. 2004 Oct; 15(10):4382-94.
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        45. Cano DA, Murcia NS, Pazour GJ, Hebrok M. Orpk mouse model of polycystic kidney disease reveals essential role of primary cilia in pancreatic tissue organization. Development. 2004 Jul; 131(14):3457-67.
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        46. Wirschell M, Pazour G, Yoda A, Hirono M, Kamiya R, Witman GB. Oda5p, a novel axonemal protein required for assembly of the outer dynein arm and an associated adenylate kinase. Mol Biol Cell. 2004 Jun; 15(6):2729-41.
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        47. Casey DM, Inaba K, Pazour GJ, Takada S, Wakabayashi K, Wilkerson CG, Kamiya R, Witman GB. DC3, the 21-kDa subunit of the outer dynein arm-docking complex (ODA-DC), is a novel EF-hand protein important for assembly of both the outer arm and the ODA-DC. Mol Biol Cell. 2003 Sep; 14(9):3650-63.
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        48. Baker SA, Freeman K, Luby-Phelps K, Pazour GJ, Besharse JC. IFT20 links kinesin II with a mammalian intraflagellar transport complex that is conserved in motile flagella and sensory cilia. J Biol Chem. 2003 Sep 5; 278(36):34211-8.
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        49. Pazour GJ, Witman GB. The vertebrate primary cilium is a sensory organelle. Curr Opin Cell Biol. 2003 Feb; 15(1):105-10.
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        50. Besharse JC, Baker SA, Luby-Phelps K, Pazour GJ. Photoreceptor intersegmental transport and retinal degeneration: a conserved pathway common to motile and sensory cilia. Adv Exp Med Biol. 2003; 533:157-64.
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        51. Pazour GJ, Rosenbaum JL. Intraflagellar transport and cilia-dependent diseases. Trends Cell Biol. 2002 Dec; 12(12):551-5.
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        52. Purton S, Pazour GJ. Meeting report: Tenth International Conference on the Cell and Molecular Biology of Chlamydomonas. Protist. 2002 Dec; 153(4):325-36.
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        53. Pazour GJ, San Agustin JT, Follit JA, Rosenbaum JL, Witman GB. Polycystin-2 localizes to kidney cilia and the ciliary level is elevated in orpk mice with polycystic kidney disease. Curr Biol. 2002 Jun 4; 12(11):R378-80.
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        54. Pazour GJ, Baker SA, Deane JA, Cole DG, Dickert BL, Rosenbaum JL, Witman GB, Besharse JC. The intraflagellar transport protein, IFT88, is essential for vertebrate photoreceptor assembly and maintenance. J Cell Biol. 2002 Apr 1; 157(1):103-13.
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        55. Pazour GJ, Witman GB. Forward and reverse genetic analysis of microtubule motors in Chlamydomonas. Methods. 2000 Dec; 22(4):285-98.
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        56. Pazour GJ, Dickert BL, Vucica Y, Seeley ES, Rosenbaum JL, Witman GB, Cole DG. Chlamydomonas IFT88 and its mouse homologue, polycystic kidney disease gene tg737, are required for assembly of cilia and flagella. J Cell Biol. 2000 Oct 30; 151(3):709-18.
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        57. Horst CJ, Fishkind DJ, Pazour GJ, Witman GB. An insertional mutant of Chlamydomonas reinhardtii with defective microtubule positioning. Cell Motil Cytoskeleton. 1999 Oct; 44(2):143-54.
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        58. Pazour GJ, Koutoulis A, Benashski SE, Dickert BL, Sheng H, Patel-King RS, King SM, Witman GB. LC2, the chlamydomonas homologue of the t complex-encoded protein Tctex2, is essential for outer dynein arm assembly. Mol Biol Cell. 1999 Oct; 10(10):3507-20.
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        59. Pazour GJ, Dickert BL, Witman GB. The DHC1b (DHC2) isoform of cytoplasmic dynein is required for flagellar assembly. J Cell Biol. 1999 Feb 8; 144(3):473-81.
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        60. Pazour GJ, Wilkerson CG, Witman GB. A dynein light chain is essential for the retrograde particle movement of intraflagellar transport (IFT). J Cell Biol. 1998 May 18; 141(4):979-92.
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        61. Koutoulis A, Pazour GJ, Wilkerson CG, Inaba K, Sheng H, Takada S, Witman GB. The Chlamydomonas reinhardtii ODA3 gene encodes a protein of the outer dynein arm docking complex. J Cell Biol. 1997 Jun 2; 137(5):1069-80.
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        62. Pazour GJ, Sineshchekov OA, Witman GB. Mutational analysis of the phototransduction pathway of Chlamydomonas reinhardtii. J Cell Biol. 1995 Oct; 131(2):427-40.
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        63. Wilkerson CG, King SM, Koutoulis A, Pazour GJ, Witman GB. The 78,000 M(r) intermediate chain of Chlamydomonas outer arm dynein isa WD-repeat protein required for arm assembly. J Cell Biol. 1995 Apr; 129(1):169-78.
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        64. Moss AG, Pazour GJ, Witman GB. Assay of Chlamydomonas phototaxis. Methods Cell Biol. 1995; 47:281-7.
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        65. Pazour GJ, Ta CN, Das A. Constitutive mutations of Agrobacterium tumefaciens transcriptional activator virG. J Bacteriol. 1992 Jun; 174(12):4169-74.
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        66. Pazour GJ, Ta CN, Das A. Mutants of Agrobacterium tumefaciens with elevated vir gene expression. Proc Natl Acad Sci U S A. 1991 Aug 15; 88(16):6941-5.
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        67. Pazour GJ, Das A. Characterization of the VirG binding site of Agrobacterium tumefaciens. Nucleic Acids Res. 1990 Dec 11; 18(23):6909-13.
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        68. Mersereau M, Pazour GJ, Das A. Efficient transformation of Agrobacterium tumefaciens by electroporation. Gene. 1990 May 31; 90(1):149-51.
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        69. Pazour GJ, Das A. virG, an Agrobacterium tumefaciens transcriptional activator, initiates translation at a UUG codon and is a sequence-specific DNA-binding protein. J Bacteriol. 1990 Mar; 172(3):1241-9.
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        70. Das A, Pazour GJ. Delineation of the regulatory region sequences of Agrobacterium tumefaciens virB operon. Nucleic Acids Res. 1989 Jun 26; 17(12):4541-50.
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        71. Sen P, Pazour GJ, Anderson D, Das A. Cooperative binding of Agrobacterium tumefaciens VirE2 protein to single-stranded DNA. J Bacteriol. 1989 May; 171(5):2573-80.
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