1. Howard Hughes Medical Institute, School and Department of Medicine, UCSD, 9500 Gilman Drive, Room 345, La Jolla, California 92093-0648, USA
2. Departments of Medicine and Pediatrics, School and Department of Medicine, UCSD, 9500 Gilman Drive, La Jolla, California 92093-0693, USA
3. Department of Cellular and Molecular Medicine, School and Department of Medicine, UCSD, 9500 Gilman Drive, La Jolla, California 92093-0651, USA
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
5. Department of Medicine/Division of Genetics, Brigham and Women's Hospital/Harvard Medical School, 20 Shattuck Street, Thorn 1010 Boston, Massachusetts 02115, USA
6. Department of Medicine, University of California, San Diego 9500, Gilman Drive, La Jolla, California 92093-0673, USA

Correspondence to: Xue Li¹Michael G. Rosenfeld¹ Email: seli@ucsd.edu
Email: mrosenfeld@ucsd.edu

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.