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Etv4 and Etv5 are required downstream of GDNF and Ret for kidney branching morphogenesis

Nature Genetics volume 41, pages 1295–1302 (2009)Cite this article

An Erratum to this article was published on 01 April 2010

This article has been updated

Abstract

Glial cell line–derived neurotrophic factor signaling through the Ret receptor tyrosine kinase is crucial for ureteric bud branching morphogenesis during kidney development, yet few of the downstream genes are known. Here we show that the ETS transcription factors Etv4 and Etv5 are positively regulated by Ret signaling in the ureteric bud tips. Mice lacking both Etv4 alleles and one Etv5 allele show either renal agenesis or severe hypodysplasia, whereas kidney development fails completely in double homozygotes. We identified several genes whose expression in the ureteric bud depends on Etv4 and Etv5, including Cxcr4, Myb, Met and Mmp14. Thus, Etv4 and Etv5 are key components of a gene network downstream of Ret that promotes and controls renal branching morphogenesis.

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Figure 1: Screen for genes upregulated by GDNF-Ret signaling in the ureteric bud.
Figure 2: Similar expression patterns of Etv4 and Etv5 during kidney development.
Figure 3: GDNF-Ret signaling regulates Etv4 and Etv5 expression in ureteric bud tips.
Figure 4: Severe renal developmental defects in newborn mice with compound Etv4 and Etv5 mutations, including two different Etv5 knockout alleles.
Figure 5: Ureteric bud branching defects in Etv4−/−; Etv5+/− compound mutants.
Figure 6: Gene expression in ureteric bud tips of Etv4−/−; Etv5+/− compound mutant kidneys.
Figure 7: Reduced Mmp14 expression in Etv4−/−; Etv5+/− compound mutant and Ret-hypomorphic kidneys.

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  • 05 February 2010

    In the version of this article initially published, the sentence under Table 1 on p. 1296 should stop after the words “and 430A arrays,” and the words “or >3 if represented on only one array” should be removed. In addition, on p. 1298, the second parenthesis after “Tg(Hoxb7-myrVenus)” is missing. These errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank S. Simonet (Amgen) for Fgf10−/− mice, K. Murphy (Washington University) for Etv5tm1Kmm mice, L. Williams and Z. Wu for technical assistance and N. Kurpios and C. Mendelsohn for critical comments on the manuscript. This work was supported by grant DK55388 (to F.C. and J.B.) and grant DK075578 (to F.C.) and by fellowships from the National Kidney Foundation (to C.C.), the American Heart Association (to X.C.) and the Sigrid Juselius Foundation and Finnish Cultural Foundation (to S.K.).

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Author notes

  1. Present addresses: Division of Hematology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland, USA (X.C.); Max-Delbrück Center for Molecular Medicine, Berlin, Germany (K.M.S.-O.); and Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, Massachusetts, USA (L.M.).

Authors and Affiliations

  1. Department of Genetics and Development, Columbia University Medical Center, New York, New York, USA

    Benson C Lu, Cristina Cebrian, Xuan Chi, Satu Kuure, Richard Kuo & Frank Costantini

  2. Division of Nephrology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, USA

    Carlton M Bates

  3. Neurobiology, Biozentrum, University of Basel, Basel, Switzerland

    Silvia Arber

  4. Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada

    John Hassell & Lesley MacNeil

  5. Department of Medicine, Renal Division, Washington University School of Medicine, St. Louis, Missouri, USA

    Masato Hoshi & Sanjay Jain

  6. Department of Pathology, Nagoya University Graduate School of Medicine, Aichi, Nagoya, Japan

    Naoya Asai & Masahide Takahashi

  7. Departments of Medicine, New York, New York, USA

    Kai M Schmidt-Ott & Jonathan Barasch

  8. Pathology, Columbia University Medical Center, New York, New York, USA

    Vivette D'Agati

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Contributions

B.C.L., C.C., X.C. and S.K. designed, conducted and interpreted experiments. R.K. conducted experiments. C.M.B., M.H., S.J., N.A. and M.T. contributed mutant kidneys. S.A., L.M. and J.H. generated the Etv5lacZ and Etv4lacZ mice. K.M.S.-O. and J.B. assisted with microarray analyses. V.D. analyzed renal histopathology. F.C. conceived and directed the project and wrote the manuscript. All authors edited the manuscript.

Corresponding author

Correspondence to Frank Costantini.

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Lu, B., Cebrian, C., Chi, X. et al. Etv4 and Etv5 are required downstream of GDNF and Ret for kidney branching morphogenesis. Nat Genet 41, 1295–1302 (2009). https://doi.org/10.1038/ng.476

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