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

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.

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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.

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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.

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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.

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

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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

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