Photo of Iain A. Drummond,  PhD

Iain A. Drummond, PhD

Massachusetts General Hospital

Massachusetts General Hospital
Phone: (617) 726-5647
Fax: (617) 726-5669


idrummond@mgh.harvard.edu

Iain A. Drummond, PhD

Massachusetts General Hospital

EDUCATIONAL TITLES

  • Associate Professor, Medicine, Harvard Medical School
  • Associate Biologist, Renal Unit, Massachusetts General Hospital

DF/HCC PROGRAM AFFILIATION

Research Abstract

We study kidney organogenesis using the zebrafish to explore conserved molecular mechanisms underlying kidney cell differentiation, morphogenesis, and regeneration. We also study organ pathologies that results from mutations in genes required for cilia biogenesis and function. These include kidney cystic disease, retinal degeneration and left-right asymmetry defects.

The zebrafish pronephros as a model of the vertebrate kidney. As part of the Boston large-scale forward genetic screens on zebrafish, we defined zebrafish pronephric kidney development and cell structure, generated assays for nephron function, and characterized fifteen different mutant loci that caused kidney cyst formation and altered epithelial membrane protein targeting. Current work examines novel kidney mutants using Next-gen sequencing to rapidly map causative mutations.

Cell signaling in kidney development and patterning. Functionally distinct kidney cell types often exist right next to each other however the developmental mechanisms driving this patterning was unknown. We showed that "salt and pepper" patterns of cell types in the zebrafish kidney are generated by Notch signaling. We went on to show that altering kidney nephron patterning by modifying Notch signaling altered kidney function. We have also defined roles for the transcription factors pax2 and osr1 in nephron segment patterning and tubule vs. endothelial cell fate. Our current work focuses on using genetically encoded fluorescent biosensors to probe cell signaling during glomerular development and capillary development.

Kidney morphogenesis and epithelial cell dynamics. The kidney convoluted proximal tubule is specialized for interaction with the kidney vasculature and segment boundary positions are tightly regulated however little was known about morphogenetic processes that control nephron development. Using live, in vivo imaging in transparent zebrafish embryos, we showed that nephron morphogenesis is driven by collective cell migration that generates proximal convolutions and defines the final position of nephron segment boundaries. Also, we showed that cell migration was signaled by the onset of nephron filtration and luminal fluid flow, linking nephron morphogenesis with nephron function. We have also used live imaging to describe tubule interconnection in the developing mouse kidney and we have shown that cell migration plays a primary role in responses to kidney injury.

Primary Ciliary Dyskinesia (PCD) is a genetic disorder affecting 1 in 15,000 births that causes cilia paralysis with left-right organ asymmetry defects, bronchiectasis, sinusitis, and infertility. Using an unbiased forward genetic approach and targeted reverse genetic approaches in zebrafish, we cloned novel cilia paralysis genes, (schmalhans / ccdc103, C21orf59, and CCDC65) and went on to show that human patient families with PCD carried mutations in orthologous human genes, identifying novel causes of PCD. A key element of this work was developing an in vivo assay to test the pathogenicity of candidate human disease alleles by mRNA injection and rescue of the zebrafish phenotype. This work established the fish as an in vivo assay system for distinguishing pathogenic human gene mutations from benign sequence polymorphisms. We have also used fish genetics to reveal new cilia mediators of tubulin post-translational modification and new insights into physiological regulation of ciliogenesis.

Kidney regeneration from adult tissue stem cells. The zebrafish has a remarkable capacity to generate new nephrons from stem cells following renal injury. To restore kidney function, filtering nephrons must connect to a tubule network to pass fluid. How cells rearrange and form new connections is not known. We are using the regenerating zebrafish kidney as a model to discover how tubule interconnections are made and to uncover signals that drive cell rearrangments required to "plumb" the kidney. Knowledge of these signals will be an important part of the molecular toolbox for growing new organs.

 

Publications

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  • Bizet AA, Becker-Heck A, Ryan R, Weber K, Filhol E, Krug P, Halbritter J, Delous M, Lasbennes MC, Linghu B, Oakeley EJ, Zarhrate M, Nitschké P, Garfa-Traore M, Serluca F, Yang F, Bouwmeester T, Pinson L, Cassuto E, Dubot P, Elshakhs NA, Sahel JA, Salomon R, Drummond IA, Gubler MC, Antignac C, Chibout S, Szustakowski JD, Hildebrandt F, Lorentzen E, Sailer AW, Benmerah A, Saint-Mezard P, Saunier S. Mutations in TRAF3IP1/IFT54 reveal a new role for IFT proteins in microtubule stabilization. Nat Commun 2015; 6:8666. PubMed
  • Yeo NC, O'Meara CC, Bonomo JA, Veth KN, Tomar R, Flister MJ, Drummond IA, Bowden DW, Freedman BI, Lazar J, Link BA, Jacob HJ. Shroom3 contributes to the maintenance of the glomerular filtration barrier integrity. Genome Res 2015. PubMed
  • Terashima AV, Mudumana SP, Drummond IA. Odd skipped related 1 is a negative feedback regulator of nodal-induced endoderm development. Dev Dyn 2014. PubMed
  • Tomar R, Mudumana SP, Pathak N, Hukriede NA, Drummond IA. osr1 is required for podocyte development downstream of wt1a. J Am Soc Nephrol 2014. PubMed
  • Slaats GG, Ghosh AK, Falke LL, Le Corre S, Shaltiel IA, van de Hoek G, Klasson TD, Stokman MF, Logister I, Verhaar MC, Goldschmeding R, Nguyen TQ, Drummond IA, Hildebrandt F, Giles RH. Nephronophthisis-associated CEP164 regulates cell cycle progression, apoptosis and epithelial-to-mesenchymal transition. PLoS Genet. 2014; 10:e1004594. PubMed
  • Jin D, Ni TT, Sun J, Wan H, Amack JD, Yu G, Fleming J, Chiang C, Li W, Papierniak A, Cheepala S, Conseil G, Cole SP, Zhou B, Drummond IA, Schuetz JD, Malicki J, Zhong TP. Prostaglandin signalling regulates ciliogenesis by modulating intraflagellar transport. Nat Cell Biol 2014; 16:841-51. PubMed
  • Le Corre S, Eyre D, Drummond IA. Modulation of the secretory pathway rescues zebrafish polycystic kidney disease pathology. J Am Soc Nephrol 2014. PubMed
  • Burger A, Vasilyev A, Tomar R, Selig MK, Nielsen GP, Peterson RT, Drummond IA, Haber DA. A zebrafish model of chordoma initiated by notochord-driven expression of HRASV12. Dis Model Mech 2014. PubMed
  • Pathak N, Austin-Tse CA, Liu Y, Vasilyev A, Drummond IA. Cytoplasmic carboxypeptidase 5 regulates tubulin glutamylation and zebrafish cilia formation and function. Mol Biol Cell 2014. PubMed
  • Thomas S, Wright KJ, Le Corre S, Micalizzi A, Romani M, Abhyankar A, Saada J, Perrault I, Amiel J, Litzler J, Filhol E, Elkhartoufi N, Kwong M, Casanova JL, Boddaert N, Baehr W, Lyonnet S, Munnich A, Burglen L, Chassaing N, Encha-Ravazi F, Vekemans M, Gleeson JG, Valente EM, Jackson PK, Drummond IA, Saunier S, Attié-Bitach T. A homozygous PDE6D mutation in Joubert syndrome impairs targeting of farnesylated INPP5E protein to the primary cilium. Hum Mutat 2014; 35:137-46. PubMed
  • Palmyre A, Lee J, Ryklin G, Camarata T, Selig MK, Duchemin AL, Nowak P, Arnaout MA, Drummond IA, Vasilyev A. Collective epithelial migration drives kidney repair after acute injury. PLoS ONE 2014; 9:e101304. PubMed
  • Lam PY, Kamei CN, Mangos S, Mudumana S, Liu Y, Drummond IA. odd-skipped related 2 is required for fin chondrogenesis in zebrafish. Dev Dyn 2013; 242:1284-92. PubMed
  • Austin-Tse C, Halbritter J, Zariwala MA, Gilberti RM, Gee HY, Hellman N, Pathak N, Liu Y, Panizzi JR, Patel-King RS, Tritschler D, Bower R, O'Toole E, Porath JD, Hurd TW, Chaki M, Diaz KA, Kohl S, Lovric S, Hwang DY, Braun DA, Schueler M, Airik R, Otto EA, Leigh MW, Noone PG, Carson JL, Davis SD, Pittman JE, Ferkol TW, Atkinson JJ, Olivier KN, Sagel SD, Dell SD, Rosenfeld M, Milla CE, Loges NT, Omran H, Porter ME, King SM, Knowles MR, Drummond IA, Hildebrandt F. Zebrafish Ciliopathy Screen Plus Human Mutational Analysis Identifies C21orf59 and CCDC65 Defects as Causing Primary Ciliary Dyskinesia. Am J Hum Genet 2013; 93:672-86. PubMed
  • Drummond IA. The cilium in lights: new views of an ancient organelle. BMC Biol 2013; 11:74. PubMed
  • Leshchiner I, Alexa K, Kelsey P, Adzhubei I, Austin-Tse CA, Cooney JD, Anderson H, King MJ, Stottmann RW, Garnaas MK, Ha S, Drummond IA, Paw BH, North TE, Beier DR, Goessling W, Sunyaev SR. Mutation mapping and identification by whole-genome sequencing. Genome Res 2012; 22:1541-8. PubMed
  • Panizzi JR, Becker-Heck A, Castleman VH, Al-Mutairi DA, Liu Y, Loges NT, Pathak N, Austin-Tse C, Sheridan E, Schmidts M, Olbrich H, Werner C, Häffner K, Hellman N, Chodhari R, Gupta A, Kramer-Zucker A, Olale F, Burdine RD, Schier AF, O'Callaghan C, Chung EM, Reinhardt R, Mitchison HM, King SM, Omran H, Drummond IA. CCDC103 mutations cause primary ciliary dyskinesia by disrupting assembly of ciliary dynein arms. Nat Genet 2012; 44:714-9. PubMed
  • Vasilyev A, Liu Y, Hellman N, Pathak N, Drummond IA. Mechanical stretch and PI3K signaling link cell migration and proliferation to coordinate epithelial tubule morphogenesis in the zebrafish pronephros. PLoS ONE 2012; 7:e39992. PubMed
  • Drummond IA. Polycystins, focal adhesions and extracellular matrix interactions. Biochim Biophys Acta 2011. PubMed
  • Pathak N, Austin CA, Drummond IA. Tubulin tyrosine ligase-like genes ttll3 and ttll6 maintain zebrafish cilia structure and motility. J Biol Chem 2011; 286:11685-95. PubMed
  • Chen LM, Zhao J, Musa-Aziz R, Pelletier MF, Drummond IA, Boron WF. Cloning and characterization of a zebrafish homologue of human AQP1: A bifunctional water and gas channel. Am J Physiol Regul Integr Comp Physiol 2010; 299:R1163-74. PubMed
  • 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. Proc Natl Acad Sci U S A 2010; 107:18499-504. PubMed
  • Sussman CR, Zhao J, Plata C, Lu J, Daly C, Angle N, DiPiero J, Drummond IA, Liang JO, Boron WF, Romero MF, Chang MH. Cloning, localization, and functional expression of the electrogenic Na+ bicarbonate cotransporter (NBCe1) from zebrafish. Am J Physiol Cell Physiol 2009; 297:C865-75. PubMed
  • Vasilyev A,Liu Y,Mudumana S,Mangos S,Lam PY,Majumdar A,Zhao J,Poon KL,Kondrychyn I,Korzh V,Drummond IA. Collective cell migration drives morphogenesis of the kidney nephron. PLoS Biol 2009; 7:e9. PubMed
  • Pathak NH, Drummond IA. Polyglutamylation and the fleer gene. Methods Cell Biol. 2010; 94:317-32. PubMed
  • Mudumana SP,Hentschel D,Liu Y,Vasilyev A,Drummond IA. odd skipped related1 reveals a novel role for endoderm in regulating kidney versus vascular cell fate. Development 2008; 135:3355-67. PubMed
  • Moller CC, Mangos S, Drummond IA, Reiser J. Expression of trpC1 and trpC6 orthologs in zebrafish. Gene Expr Patterns 2008; 8:291-296. PubMed
  • Insinna C, Pathak N, Perkins B, Drummond I, Besharse JC. The homodimeric kinesin, Kif17, is essential for vertebrate photoreceptor sensory outer segment development. Dev Biol 2008; 316:160-70. PubMed
  • Pathak N, Obara T, Mangos S, Liu Y, Drummond IA. The zebrafish fleer gene encodes an essential regulator of cilia tubulin polyglutamylation. Mol Biol Cell 2007; 18:4353-64. PubMed
  • Panizzi JR, Jessen JR, Drummond IA, Solnica-Krezel L. New functions for a vertebrate Rho guanine nucleotide exchange factor in ciliated epithelia. Development 2007; 134:921-31. PubMed
  • Liu Y, Pathak N, Kramer-Zucker A, Drummond IA. Notch signaling controls the differentiation of transporting epithelia and multiciliated cells in the zebrafish pronephros. Development 2007; 134:1111-22. PubMed
  • Hinkes B, Wiggins RC, Gbadegesin R, Vlangos CN, Seelow D, Nurnberg G, Garg P, Verma R, Chaib H, Hoskins BE, Ashraf S, Becker C, Hennies HC, Goyal M, Wharram BL, Schachter AD, Mudumana S, Drummond I, Kerjaschki D, Waldherr R, Dietrich A, Ozaltin F, Bakkaloglu A, Cleper R, Basel-Vanagaite L, Pohl M, Griebel M, Tsygin AN, Soylu A, Muller D, Sorli CS, Bunney TD, Katan M, Liu J, Attanasio M, O'toole JF, Hasselbacher K, Mucha B, Otto EA, Airik R, Kispert A, Kelley GG, Smrcka AV, Gudermann T, Holzman LB, Nurnberg P, Hildebrandt F. Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible. Nat Genet 2006; 38:1397-405. PubMed
  • Obara T, Mangos S, Liu Y, Zhao J, Wiessner S, Kramer-Zucker AG, Olale F, Schier AF, Drummond IA. Polycystin-2 immunolocalization and function in zebrafish. J Am Soc Nephrol 2006; 17:2706-18. PubMed
  • Sayer JA, Otto EA, O'Toole JF, Nurnberg G, Kennedy MA, Becker C, Hennies HC, Helou J, Attanasio M, Fausett BV, Utsch B, Khanna H, Liu Y, Drummond I, Kawakami I, Kusakabe T, Tsuda M, Ma L, Lee H, Larson RG, Allen SJ, Wilkinson CJ, Nigg EA, Shou C, Lillo C, Williams DS, Hoppe B, Kemper MJ, Neuhaus T, Parisi MA, Glass IA, Petry M, Kispert A, Gloy J, Ganner A, Walz G, Zhu X, Goldman D, Nurnberg P, Swaroop A, Leroux MR, Hildebrandt F. The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4. Nat Genet 2006; 38:674-81. PubMed
  • Mangos S, Lam PY, Zhao A, Liu Y, Mudumana S, Vasilyev A, Liu A, Drummond IA. The ADPKD genes pkd1a/b and pkd2 regulate extracellular matrix formation. Dis Model Mech 2010; 3:354-65. PubMed
  • Vasilyev A, Drummond IA. Fluid flow and guidance of collective cell migration. Cell Adh Migr 2010; 4:353-7. PubMed
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