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Eya protein phosphatase activity regulates Six1–Dach–Eya transcriptional effects in mammalian organogenesis

Nature volume 426, pages 247–254 (2003)Cite this article

A Corrigendum to this article was published on 15 January 2004

Abstract

The precise mechanistic relationship between gene activation and repression events is a central question in mammalian organogenesis, as exemplified by the evolutionarily conserved sine oculis (Six), eyes absent (Eya) and dachshund (Dach) network of genetically interacting proteins. Here, we report that Six1 is required for the development of murine kidney, muscle and inner ear, and that it exhibits synergistic genetic interactions with Eya factors. We demonstrate that the Eya family has a protein phosphatase function, and that its enzymatic activity is required for regulating genes encoding growth control and signalling molecules, modulating precursor cell proliferation. The phosphatase function of Eya switches the function of Six1–Dach from repression to activation, causing transcriptional activation through recruitment of co-activators. The gene-specific recruitment of a co-activator with intrinsic phosphatase activity provides a molecular mechanism for activation of specific gene targets, including those regulating precursor cell proliferation and survival in mammalian organogenesis.

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Figure 1: Six1 is required for the development of multiple organs.
Figure 2: Molecular analyses of the developmental muscle and kidney defects.
Figure 3: Decreased cell proliferation, increased cell death and diminished c-Myc gene expression.
Figure 4: Eya has intrinsic phosphatase activity and this is required for Six1-mediated gene activation and cell proliferation.
Figure 5: Eya3 phosphatase activity is required to recruit CBP and relieve Dach-mediated repression.
Figure 6: Genetic interaction between Six1 and Eya1 in regulating muscle, pituitary and kidney development.

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Acknowledgements

We thank G. N. Gill, J. E. Dixon, M. Yeo, L. Erkman, V. Perissi, L. Olson, F. Liu and V. Kumar for reagents, critical advice and suggestions; P. Myer and M. Fisher for figure and manuscript preparation; C. Nelson for tissue culture; P. Kotol for technical assistance; and H. Taylor for animal care. We are grateful to those who provided us with essential reagents for this study. This work was supported by grants from the NIH to X.L., M.G.R., D.W.R., R.M., A.K.A. and S.K.N. M.G.R. is an investigator with the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Howard Hughes Medical Institute, School and Department of Medicine, UCSD, 9500 Gilman Drive, Room 345, La Jolla, California, 92093-0648, USA

    Xue Li, Kenneth A. Ohgi, Jie Zhang, Anna Krones & Michael G. Rosenfeld

  2. Departments of Medicine and Pediatrics, School and Department of Medicine, UCSD, 9500 Gilman Drive, La Jolla, California, 92093-0693, USA

    Kevin T. Bush & Sanjay K. Nigam

  3. Department of Cellular and Molecular Medicine, School and Department of Medicine, UCSD, 9500 Gilman Drive, La Jolla, California, 92093-0651, USA

    Christopher K. Glass

  4. Structural Biology Program, Department of Physiology and Biophysics, Mount Sinai School of Medicine, Box 1677, 1425 Madison Avenue, New York, New York, 10029-6574, USA

    Aneel K. Aggarwal

  5. Department of Medicine/Division of Genetics, Brigham and Women's Hospital/Harvard Medical School, 20 Shattuck Street, Thorn 1010, Boston, Massachusetts, 02115, USA

    Richard Maas

  6. Department of Medicine, University of California, San Diego 9500, Gilman Drive, La Jolla, California, 92093-0673, USA

    David W. Rose

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Li, X., Ohgi, K., Zhang, J. et al. Eya protein phosphatase activity regulates Six1–Dach–Eya transcriptional effects in mammalian organogenesis. Nature 426, 247–254 (2003). https://doi.org/10.1038/nature02083

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