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Wnt9b signaling regulates planar cell polarity and kidney tubule morphogenesis

Nature Genetics volume 41, pages 793–799 (2009)Cite this article

Abstract

Although many vertebrate organs, such as kidneys, lungs and liver, are composed of epithelial tubules, little is known of the mechanisms that establish the length or diameter of these tubules. In the kidney, defects in the establishment or maintenance of tubule diameter are associated with one of the most common inherited human disorders, polycystic kidney disease. Here we show that attenuation of Wnt9b signaling during kidney morphogenesis affects the planar cell polarity of the epithelium and leads to tubules with significantly increased diameter. Although previous studies showed that polarized cell divisions maintain the diameter of postnatal kidney tubules, we find that cell divisions are randomly oriented during embryonic development. Our data suggest that diameter is established during early morphogenetic stages by convergent extension processes and maintained by polarized cell divisions. Wnt9b, signaling through the non-canonical Rho/Jnk branch of the Wnt pathway, is necessary for both of these processes.

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Figure 1: Defects in Wnt9b signaling results in cyst formation.
Figure 2: Characterization of cyst origin in Wnt9bneo/neo kidneys.
Figure 3: Cell division becomes oriented after birth in a Wnt9b-dependent process.
Figure 4: Wnt9b is required for the elongation and narrowing of kidney tubules.
Figure 5: Wnt9b is necessary for the orientation of polarized cells perpendicular to the axis of extension.
Figure 6: Wnt9b signals through the noncanonical pathway to regulate tubule diameter.

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Acknowledgements

We thank O. Cleaver for reading and commenting on this manuscript, L. Avery for help with statistical analysis, J. Zhou (Brigham and Women's and Harvard Medical School) for providing us with antibodies to Pc-1 and Pc-2 and the Pkd1 mutant kidneys, M. Taketo (Kyoto University) for providing the beta-catenin exon 3 flox mice, O. Cabello (J.H. Quillen College of Medicine, East Tennessee State University) for providing us with the Invs mutant kidneys, B. Adams, E. Small, J. Shelton and the Molecular Pathology Core for technical assistance and L. James and M. Princena for the urine albumin studies. This work was supported by grants from the American Society for Nephrology, the American Heart Association (0730236N), the Polycystic Kidney Disease Research Foundation, the UAB ARPKD Center (5P30DK07403802) and the US National Institutes of Health (1R01DK080004) to T.J.C. The work was also supported by the University of Texas Southwestern O'Brien Kidney Research Core Center (NIH P30DK079328). J.B.W. was supported by grants from the National Institute for General Medical Sciences, the March of Dimes and the Burroughs Wellcome Fund.

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Authors and Affiliations

  1. Department of Internal Medicine, Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Courtney M Karner, Rani Chirumamilla, Shigehisa Aoki, Peter Igarashi & Thomas J Carroll

  2. Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Courtney M Karner, Rani Chirumamilla & Thomas J Carroll

  3. Pathology & Biodefense Faculty of Medicine, Saga University, Saga, Japan

    Shigehisa Aoki

  4. Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Peter Igarashi

  5. Molecular, Cell and Developmental Biology & Institute for Cellular and Molecular Biology, University of Texas, Austin, Austin, Texas, USA

    John B Wallingford

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  1. Courtney M Karner
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Contributions

C.M.K. designed experiments, performed experiments, assembled data and wrote the manuscript, R.C. performed biochemistry, S.A. assisted with quantitative analysis on Wnt9bneo/neo kidneys, P.I. provided KspCre mice and commented on manuscript, J.B.W. assisted with cell orientation analysis and T.J.C. performed initial experiments, designed experiments and wrote the manuscript.

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Correspondence to Thomas J Carroll.

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Karner, C., Chirumamilla, R., Aoki, S. et al. Wnt9b signaling regulates planar cell polarity and kidney tubule morphogenesis. Nat Genet 41, 793–799 (2009). https://doi.org/10.1038/ng.400

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