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Gene Review

Ift88  -  intraflagellar transport 88

Mus musculus

Synonyms: AW552028, IFT88, Intraflagellar transport protein 88 homolog, Oak Ridge polycystic kidneys, Recessive polycystic kidney disease protein Tg737, ...
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Disease relevance of Ift88

  • The Oak Ridge Polycystic Kidney (orpk) mouse contains a mutated Tg737 gene that disrupts expression of polaris, a protein required for ciliogenesis [1].
  • Unlike the orpk allele, where all homozygotes survive to birth, embryos homozygous for the Tg737(Delta)2-3(beta)Gal) mutation arrest in development at mid-gestation and exhibit neural tube defects, enlargement of the pericardial sac and, most notably, left-right asymmetry defects [2].
  • We further find that mice with a mutation in the IFT particle protein gene, Tg737/IFT88, have abnormal OS development and retinal degeneration [3].
  • The C. elegans homolog of the murine cystic kidney disease gene Tg737 functions in a ciliogenic pathway and is disrupted in osm-5 mutant worms [4].
  • The liver pathology in TgN737Rpw mice is characterized by a biliary hyperplasia that includes the proliferation of cells that morphologically and immunologically resemble oval cells, a liver progenitor cell [5].

High impact information on Ift88


Biological context of Ift88

  • The differences in the phenotype between the two mutations suggest that the orpk mutation is a hypomorphic allele of the Tg737 gene [2].
  • Analysis of this new knockout allele allows us to define a critical role for the Tg737 gene during early embryogenesis [2].
  • Here we show that in orpk mice, a model system for PKD that harbors a mutation in the gene that encodes the polaris protein, pancreatic defects start to occur at the end of gestation, with an initial expansion of the developing pancreatic ducts [10].
  • Here we report that homozygous mutants for flexo (Fxo), a hypomorphic allele of mouse IFT88 generated in our ENU mutagenesis screen, exhibit polydactyly in all four limbs [11].
  • Oval cell proliferation associated with the murine insertional mutation TgN737Rpw [5].

Anatomical context of Ift88

  • In the orpk pancreas, cilia numbers are reduced and cilia length is decreased [10].
  • Similar to murine polaris, the OSM-5 protein was found to concentrate at the cilium base and within the cilium axoneme as shown by an OSM-5::GFP translational fusion and immunofluorescence [4].
  • A cortical collecting duct cell line has been derived from mice with a mutation in the Tg737 gene [12].
  • In early limb buds, Tg737 expression is detected throughout the mesenchyme becoming concentrated in precartilage condensations at later stages [13].
  • These data indicate that kidney tubules require a threshold level of Tg737 function for normal tubular development, structure, and function [14].

Associations of Ift88 with chemical compounds

  • This study sought to determine whether the mammalian polycystins are expressed in primary cilia of renal epithelia and whether these proteins co-localize with polaris and cystin, the newly described, cilia-associated protein that is disrupted in the cpk mouse [15].
  • These findings are interesting in light of the recently proposed role for polaris, the protein encoded by the Tg737 gene, in the hedgehog pathway and hedgehog signaling in insulin production and glucose homeostasis [16].
  • Together, these data suggest that ENaC expression and/or function are upregulated in the luminal membrane of mutant, cilium-deficient orpk CCD PC monolayers vs. cilium-competent controls [17].
  • Effect of polysaccharide extracted from Glaciecola polaris on the protection of mouse macrophages from oxidative injury [18].

Other interactions of Ift88

  • Immunofluorescence studies revealed that PC2, normally expressed on and at the base of cilia in orpk cilia(+) cells, was observed throughout the apical membrane in cilia(-) cells [1].
  • Genetic analysis shows that Wim, Polaris and the IFT motor protein Kif3a are required for Hedgehog signalling at a step downstream of Patched1 (the Hedgehog receptor) and upstream of direct targets of Hedgehog signalling [19].
  • Thus, polaris and primary cilia function are required for the maturation and maintenance of proper tissue organization in the pancreas [10].
  • Further analysis of the orpk mouse model of human autosomal recessive polycystic kidney disease is providing more insight into the function of the Tg737 gene and the pathobiology of renal cystic disease [14].
  • Anomalous structure of primary cilia and/or impairment of increases in intracellular Ca2+ concentration in response to fluid flow are thought to result in renal cyst formation in conditional kif3a knockout, Tg737 and pkd1/pkd2 mutant mice [20].

Analytical, diagnostic and therapeutic context of Ift88

  • Complementation tests between the original orpk mutation and the new targeted knock-out mutation demonstrate that Tg737(Delta)2-3(beta)Gal) behaves as an allele of Tg737 [2].
  • Using the in situ hybridization procedure, expression of the Tg737 mRNA can be detected in the collecting ducts of adult kidneys and in portions of the embryonic day 15.5 kidney [21].
  • Expression of the Tg737 gene can normally be detected using the Northern blot analysis at low levels in a variety of tissues, including the kidney and liver [21].
  • Scanning electron microscopy was utilized to observe and measure cilia expression in cysts from orpk, orpk rescue, and KO rescue animals [22].


  1. Loss of primary cilia results in deregulated and unabated apical calcium entry in ARPKD collecting duct cells. Siroky, B.J., Ferguson, W.B., Fuson, A.L., Xie, Y., Fintha, A., Komlosi, P., Yoder, B.K., Schwiebert, E.M., Guay-Woodford, L.M., Bell, P.D. Am. J. Physiol. Renal Physiol. (2006) [Pubmed]
  2. The Oak Ridge Polycystic Kidney (orpk) disease gene is required for left-right axis determination. Murcia, N.S., Richards, W.G., Yoder, B.K., Mucenski, M.L., Dunlap, J.R., Woychik, R.P. Development (2000) [Pubmed]
  3. The intraflagellar transport protein, IFT88, is essential for vertebrate photoreceptor assembly and maintenance. Pazour, G.J., Baker, S.A., Deane, J.A., Cole, D.G., Dickert, B.L., Rosenbaum, J.L., Witman, G.B., Besharse, J.C. J. Cell Biol. (2002) [Pubmed]
  4. The C. elegans homolog of the murine cystic kidney disease gene Tg737 functions in a ciliogenic pathway and is disrupted in osm-5 mutant worms. Haycraft, C.J., Swoboda, P., Taulman, P.D., Thomas, J.H., Yoder, B.K. Development (2001) [Pubmed]
  5. Oval cell proliferation associated with the murine insertional mutation TgN737Rpw. Richards, W.G., Yoder, B.K., Isfort, R.J., Detilleux, P.G., Foster, C., Neilsen, N., Woychik, R.P., Wilkinson, J.E. Am. J. Pathol. (1996) [Pubmed]
  6. Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nauli, S.M., Alenghat, F.J., Luo, Y., Williams, E., Vassilev, P., Li, X., Elia, A.E., Lu, W., Brown, E.M., Quinn, S.J., Ingber, D.E., Zhou, J. Nat. Genet. (2003) [Pubmed]
  7. Chlamydomonas IFT88 and its mouse homologue, polycystic kidney disease gene tg737, are required for assembly of cilia and flagella. Pazour, G.J., Dickert, B.L., Vucica, Y., Seeley, E.S., Rosenbaum, J.L., Witman, G.B., Cole, D.G. J. Cell Biol. (2000) [Pubmed]
  8. Cilia and Hedgehog responsiveness in the mouse. Huangfu, D., Anderson, K.V. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  9. Expression analyses and interaction with the anaphase promoting complex protein Apc2 suggest a role for inversin in primary cilia and involvement in the cell cycle. Morgan, D., Eley, L., Sayer, J., Strachan, T., Yates, L.M., Craighead, A.S., Goodship, J.A. Hum. Mol. Genet. (2002) [Pubmed]
  10. Orpk mouse model of polycystic kidney disease reveals essential role of primary cilia in pancreatic tissue organization. Cano, D.A., Murcia, N.S., Pazour, G.J., Hebrok, M. Development (2004) [Pubmed]
  11. Mouse intraflagellar transport proteins regulate both the activator and repressor functions of Gli transcription factors. Liu, A., Wang, B., Niswander, L.A. Development (2005) [Pubmed]
  12. Polaris, a protein disrupted in orpk mutant mice, is required for assembly of renal cilium. Yoder, B.K., Tousson, A., Millican, L., Wu, J.H., Bugg, C.E., Schafer, J.A., Balkovetz, D.F. Am. J. Physiol. Renal Physiol. (2002) [Pubmed]
  13. Loss of the Tg737 protein results in skeletal patterning defects. Zhang, Q., Murcia, N.S., Chittenden, L.R., Richards, W.G., Michaud, E.J., Woychik, R.P., Yoder, B.K. Dev. Dyn. (2003) [Pubmed]
  14. Expression of the orpk disease gene during kidney development and maturation. Nakanishi, K., Sweeney, W.E., Avner, E.D., Murcia, N.S. Pediatr. Nephrol. (2001) [Pubmed]
  15. The polycystic kidney disease proteins, polycystin-1, polycystin-2, polaris, and cystin, are co-localized in renal cilia. Yoder, B.K., Hou, X., Guay-Woodford, L.M. J. Am. Soc. Nephrol. (2002) [Pubmed]
  16. Disruption of IFT results in both exocrine and endocrine abnormalities in the pancreas of Tg737(orpk) mutant mice. Zhang, Q., Davenport, J.R., Croyle, M.J., Haycraft, C.J., Yoder, B.K. Lab. Invest. (2005) [Pubmed]
  17. Heightened epithelial Na+ channel-mediated Na+ absorption in a murine polycystic kidney disease model epithelium lacking apical monocilia. Olteanu, D., Yoder, B.K., Liu, W., Croyle, M.J., Welty, E.A., Rosborough, K., Wyss, J.M., Bell, P.D., Guay-Woodford, L.M., Bevensee, M.O., Satlin, L.M., Schwiebert, E.M. Am. J. Physiol., Cell Physiol. (2006) [Pubmed]
  18. Effect of polysaccharide extracted from Glaciecola polaris on the protection of mouse macrophages from oxidative injury. Qian, G., Xu, Z. Bioresour. Technol. (2007) [Pubmed]
  19. Hedgehog signalling in the mouse requires intraflagellar transport proteins. Huangfu, D., Liu, A., Rakeman, A.S., Murcia, N.S., Niswander, L., Anderson, K.V. Nature (2003) [Pubmed]
  20. Primary cilia of inv/inv mouse renal epithelial cells sense physiological fluid flow: bending of primary cilia and Ca2+ influx. Shiba, D., Takamatsu, T., Yokoyama, T. Cell Struct. Funct. (2005) [Pubmed]
  21. Insertional mutagenesis and molecular analysis of a new gene associated with polycystic kidney disease. Yoder, B.K., Richards, W.G., Sweeney, W.E., Wilkinson, J.E., Avener, E.D., Woychik, R.P. Proc. Assoc. Am. Physicians (1995) [Pubmed]
  22. Delayed cystogenesis and increased ciliogenesis associated with the re-expression of polaris in Tg737 mutant mice. Brown, N.E., Murcia, N.S. Kidney Int. (2003) [Pubmed]
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