Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Loss of Fat4 disrupts PCP signaling and oriented cell division and leads to cystic kidney disease

Nature Genetics volume 40, pages 1010–1015 (2008)Cite this article

Abstract

Tissue organization in Drosophila is regulated by the core planar cell polarity (PCP) proteins Frizzled, Dishevelled, Prickle, Van Gogh and Flamingo. Core PCP proteins are conserved in mammals and function in mammalian tissue organization. Recent studies have identified another group of Drosophila PCP proteins, consisting of the protocadherins Fat and Dachsous (Ds) and the transmembrane protein Four-jointed (Fj). In Drosophila, Fat represses fj transcription, and Ds represses Fat activity in PCP. Here we show that Fat4 is an essential gene that has a key role in vertebrate PCP. Loss of Fat4 disrupts oriented cell divisions and tubule elongation during kidney development, leading to cystic kidney disease. Fat4 genetically interacts with the PCP genes Vangl2 and Fjx1 in cyst formation. In addition, Fat4 represses Fjx1 expression, indicating that Fat signaling is conserved. Together, these data suggest that Fat4 regulates vertebrate PCP and that loss of PCP signaling may underlie some cystic diseases in humans.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Fat4−/− mutants have a short body with loop-tails and small kidneys.
Figure 2: Loss of Fat4 leads to PCP defects.
Figure 3: Loss of Fat4 results in cystic kidney disease.
Figure 4: Defects in PCP signaling, oriented cell division and tubule elongation in Fat4 mutant kidneys.
Figure 5: Genetic interaction of Fat4 with Vangl2 and Fjx1 in cyst formation.

References

  1. Seifert, J.R. & Mlodzik, M. Frizzled/PCP signalling: a conserved mechanism regulating cell polarity and directed motility. Nat. Rev. Genet. 8, 126–138 (2007).

    Article  CAS  PubMed  Google Scholar 

  2. Saburi, S. & McNeill, H. Organising cells into tissues: new roles for cell adhesion molecules in planar cell polarity. Curr. Opin. Cell Biol. 17, 482–488 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. Montcouquiol, M. et al. Identification of Vangl2 and Scrb1 as planar polarity genes in mammals. Nature 423, 173–177 (2003).

    Article  CAS  PubMed  Google Scholar 

  4. Curtin, J.A. et al. Mutation of Celsr1 disrupts planar polarity of inner ear hair cells and causes severe neural tube defects in the mouse. Curr. Biol. 13, 1129–1133 (2003).

    Article  CAS  PubMed  Google Scholar 

  5. Park, T.J., Haigo, S.L. & Wallingford, J.B. Ciliogenesis defects in embryos lacking inturned or fuzzy function are associated with failure of planar cell polarity and Hedgehog signaling. Nat. Genet. 38, 303–311 (2006).

    Article  CAS  PubMed  Google Scholar 

  6. Zeidler, M.P., Perrimon, N. & Strutt, D.I. The four-jointed gene is required in the Drosophila eye for ommatidial polarity specification. Curr. Biol. 9, 1363–1372 (1999).

    Article  CAS  PubMed  Google Scholar 

  7. Casal, J., Struhl, G. & Lawrence, P.A. Developmental compartments and planar polarity in Drosophila. Curr. Biol. 12, 1189–1198 (2002).

    Article  CAS  PubMed  Google Scholar 

  8. Rawls, A.S., Guinto, J.B. & Wolff, T. The cadherins fat and dachsous regulate dorsal/ventral signaling in the Drosophila eye. Curr. Biol. 12, 1021–1026 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Yang, C.H., Axelrod, J.D. & Simon, M.A. Regulation of Frizzled by fat-like cadherins during planar polarity signaling in the Drosophila compound eye. Cell 108, 675–688 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. Fanto, M. et al. The tumor-suppressor and cell adhesion molecule Fat controls planar polarity via physical interactions with Atrophin, a transcriptional co-repressor. Development 130, 763–774 (2003).

    Article  CAS  PubMed  Google Scholar 

  11. Simon, M.A. Planar cell polarity in the Drosophila eye is directed by graded Four-jointed and Dachsous expression. Development 131, 6175–6184 (2004).

    Article  CAS  PubMed  Google Scholar 

  12. Matakatsu, H. & Blair, S.S. Separating the adhesive and signaling functions of the Fat and Dachsous protocadherins. Development 133, 2315–2324 (2006).

    Article  CAS  PubMed  Google Scholar 

  13. Matakatsu, H. & Blair, S.S. Interactions between Fat and Dachsous and the regulation of planar cell polarity in the Drosophila wing. Development 131, 3785–3794 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Ma, D., Yang, C.H., McNeill, H., Simon, M.A. & Axelrod, J.D. Fidelity in planar cell polarity signalling. Nature 421, 543–547 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. Casal, J., Lawrence, P.A. & Struhl, G. Two separate molecular systems, Dachsous/Fat and Starry night/Frizzled, act independently to confer planar cell polarity. Development 133, 4561–4572 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. Rock, R., Schrauth, S. & Gessler, M. Expression of mouse dchs1, fjx1, and fat-j suggests conservation of the planar cell polarity pathway identified in Drosophila. Dev. Dyn. 234, 747–755 (2005).

    Article  CAS  PubMed  Google Scholar 

  17. Jones, C. & Chen, P. Planar cell polarity signaling in vertebrates. Bioessays 29, 120–132 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Wang, Y., Guo, N. & Nathans, J. The role of Frizzled3 and Frizzled6 in neural tube closure and in the planar polarity of inner-ear sensory hair cells. J. Neurosci. 26, 2147–2156 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Gong, Y., Mo, C. & Fraser, S.E. Planar cell polarity signalling controls cell division orientation during zebrafish gastrulation. Nature 430, 689–693 (2004).

    Article  CAS  PubMed  Google Scholar 

  20. Baena-Lopez, L.A., Baonza, A. & Garcia-Bellido, A. The orientation of cell divisions determines the shape of Drosophila organs. Curr. Biol. 15, 1640–1644 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. Fischer, E. et al. Defective planar cell polarity in polycystic kidney disease. Nat. Genet. 38, 21–23 (2006).

    Article  CAS  PubMed  Google Scholar 

  22. Probst, B., Rock, R., Gessler, M., Vortkamp, A. & Puschel, A.W. The rodent Four-jointed ortholog Fjx1 regulates dendrite extension. Dev. Biol. 312, 461–470 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Kume, T., Deng, K. & Hogan, B.L. Murine forkhead/winged helix genes Foxc1 (Mf1) and Foxc2 (Mfh1) are required for the early organogenesis of the kidney and urinary tract. Development 127, 1387–1395 (2000).

    CAS  PubMed  Google Scholar 

  24. Ciani, L., Patel, A., Allen, N.D. & ffrench-Constant, C. Mice lacking the giant protocadherin mFAT1 exhibit renal slit junction abnormalities and a partially penetrant cyclopia and anophthalmia phenotype. Mol. Cell. Biol. 23, 3575–3582 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Nauli, S.M. et al. Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat. Genet. 33, 129–137 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. Yoder, B.K. Role of primary cilia in the pathogenesis of polycystic kidney disease. J. Am. Soc. Nephrol. 18, 1381–1388 (2007).

    Article  CAS  PubMed  Google Scholar 

  27. Hildebrandt, F. & Otto, E. Cilia and centrosomes: a unifying pathogenic concept for cystic kidney disease? Nat. Rev. Genet. 6, 928–940 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Patel, V. et al. Acute kidney injury and aberrant planar cell polarity induce cyst formation in mice lacking renal cilia. Hum. Mol. Genet. 17, 1578–1590 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Torres, V.E. & Harris, P.C. Mechanisms of disease: autosomal dominant and recessive polycystic kidney diseases. Nat. Clin. Pract. Nephrol. 2, 40–55 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. Simons, M. & Walz, G. Polycystic kidney disease: cell division without a c(l)ue? Kidney Int. 70, 854–864 (2006).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to I. Rosewell of Cancer Research UK for help in generating the Fat4 germline chimeras. We also thank J. Hoyer (University of Delaware), M. Knepper (National Heart, Lung, and Blood Institute), T. Carroll (University of Texas Southwestern), B. Bruneau (University of California, San Francisco) and the Developmental Studies Hybridoma bank for antibodies and probes, J. Johnson (University of Texas Southwestern) for the Math-1-GFP mice, P. Gros (McGill University) for mice and antibodies and A. Vortkamp (Universitaet Duisburg-Essen) for help with generating the Fjx1-null mice. This work was supported by grants from the Canadian Institute for Health Research (MOP84468) and Cancer Research UK to H.M. and from the Fondation pour la Recherche Medical and PKD foundation to M.P. We apologize to those whose work we were unable to cite because of space constraints.

Author information

Authors and Affiliations

  1. Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, Toronto, M5G 1X5, Canada

    Sakura Saburi, Ian Hester, Vera Eremina, Sue E Quaggin & Helen McNeill

  2. Developmental Biology Department, 'Gene Expression Development and Disease' Laboratory, Centre National de la Recherche Scientifique URA 2578, Pasteur Institute, Paris, France.,

    Evelyne Fischer & Marco Pontoglio

  3. Theodor-Boveri-Institute of the University of Wuerzburg, Wuerzburg, D-97074, Germany

    Manfred Gessler

  4. St. Michael's Hospital, Toronto, M5G 1X5, Canada

    Sue E Quaggin

  5. Hospital for Sick Children, Toronto, M5G 1X8, Canada

    Robert Harrison & Richard Mount

  6. Department of Molecular Genetics, University of Toronto, Toronto, M5G 1X5, Canada

    Helen McNeill

Authors
  1. Sakura Saburi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ian Hester
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Evelyne Fischer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marco Pontoglio
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Vera Eremina
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Manfred Gessler
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sue E Quaggin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Robert Harrison
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Richard Mount
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Helen McNeill
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.S. and H.M. designed the experiments, analyzed the data and wrote the paper. M.G. provided mice. R.M. and R.H. analyzed the inner ear phenotype. S.S., V.E. and I.H. conducted the in situ hybridizations. E.F. and M.P. analyzed spindle orientation. S.S. analyzed the cochlea elongation phenotype, neural tube phenotype and cystic kidney morphometric analysis. S.E.Q. helped in the analysis of cystic kidney phenotypes. S.S. and I.H. conducted the immunohistochemistry.

Corresponding author

Correspondence to Helen McNeill.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6, Supplementary Tables 1 and 2, Supplementary Methods (PDF 2291 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Saburi, S., Hester, I., Fischer, E. et al. Loss of Fat4 disrupts PCP signaling and oriented cell division and leads to cystic kidney disease. Nat Genet 40, 1010–1015 (2008). https://doi.org/10.1038/ng.179

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.179

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing