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Molecular and Cellular Biology, September 2003, p. 5989-5999, Vol. 23, No. 17
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.17.5989-5999.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Functional Dissection of Eyes absent Reveals New Modes of Regulation within the Retinal Determination Gene Network

Serena J. Silver,1,2 Erin L. Davies,1,{dagger} Laura Doyon,1 and Ilaria Rebay1,2*

Whitehead Institute for Biomedical Research,1 MIT Department of Biology, Cambridge, Massachusetts 021422

Received 26 December 2002/ Returned for modification 18 February 2003/ Accepted 19 May 2003

The retinal determination (RD) gene network encodes a group of transcription factors and cofactors necessary for eye development. Transcriptional and posttranslational regulation of RD family members is achieved through interactions within the network and with extracellular signaling pathways, including epidermal growth factor receptor/RAS/mitogen-activated protein kinase (MAPK), transforming growth factor ß/DPP, Wingless, Hedgehog, and Notch. Here we present the results of structure-function analyses that reveal novel aspects of Eyes absent (EYA) function and regulation. We find that the conserved C-terminal EYA domain negatively regulates EYA transactivation potential, and that GROUCHO-SINE OCULIS (SO) interactions provide another mechanism for negative regulation of EYA-SO target genes. We have mapped the transactivation potential of EYA to an internal proline-, serine-, and threonine-rich region that includes the EYA domain 2 (ED2) and two MAPK phosphorylation consensus sites and demonstrate that activation of the RAS/MAPK pathway potentiates transcriptional output of EYA and the EYA-SO complex in certain contexts. Drosophila S2 cell two-hybrid assays were used to describe a novel homotypic interaction that is mediated by EYA's N terminus. Our data suggest that EYA requires homo- and heterotypic interactions and RAS/MAPK signaling responsiveness to ensure context-appropriate RD gene network activity.

* Corresponding author. Mailing address: Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142. Phone: (617) 258-6399. Fax: (617) 258-0376. E-mail: rebay{at}wi.mit.edu.

{dagger} Present address: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305.

Molecular and Cellular Biology, September 2003, p. 5989-5999, Vol. 23, No. 17
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.17.5989-5999.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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