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Drosophila eye specification and development relies on a collection of transcription factors termed the retinal determination gene network (RDGN). Two members of this network, Eyes absent (EYA) and Sine oculis (SO), form a transcriptional complex in which EYA provides the transactivation function while SO provides the DNA binding activity. EYA also functions as a protein tyrosine phosphatase, raising the question of whether transcriptional output is dependent or independent of phosphatase activity. To explore this, we used microarrays together with binding site analysis, quantitative real-time PCR, chromatin immunoprecipitation, genetics and in vivo expression analysis to identify new EYA-SO targets. In parallel, we examined the expression profiles of tissue expressing phosphatase mutant eya and found that reducing phosphatase activity did not globally impair transcriptional output. Among the targets identified by our analysis was the cell cycle regulatory gene, string (stg), suggesting that EYA and SO may influence cell proliferation through transcriptional regulation of stg. Future investigation into the regulation of stg and other EYA-SO targets identified in this study will help elucidate the transcriptional circuitries whereby output from the RDGN integrates with other signaling inputs to coordinate retinal development.

Integration of multiple signaling pathways at the level of their transcriptional effectors provides an important strategy for fine-tuning gene expression and ensuring a proper program of development. Posttranslational modifications, such as phosphorylation, play important roles in modulating transcription factor activity. The discovery that the transcription factor Eyes absent (Eya) possesses protein phosphatase activity provides an interesting new paradigm. Eya may regulate the phosphorylation state of either itself or its transcriptional cofactors, thereby directly affecting transcriptional output. The identification of a growing number of transcription factors with enzymic activity suggests that such dual-function proteins exert greater control of signaling events than previously imagined. Given the conservation of both its phosphatase and transcription factor activity across mammalian species, Eya provides an excellent model for studying how a single protein integrates these two functions under the influence of multiple signaling pathways to promote development.