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Drosophila TGIF Proteins Are Transcriptional Activators

Department of Biochemistry and Molecular Genetics, and Center for Cell Signaling, University of Virginia, Charlottesville, Virginia 22908,¹ Department of Biology and Graduate Program in Molecular and Cellular Biology, Arizona State University, Tempe, Arizona 85287²

Received 21 March 2003/ Returned for modification 29 May 2003/ Accepted 3 September 2003

The information carried by transforming growth factor ß (TGF-ß) signaling molecules induces profound responses in target cells. To restrict this information to appropriate cells, TGF-ß signaling pathways are tightly regulated by dynamic interactions with transcriptional activators and repressors. Numerous cross-species experiments have shown that TGF-ß family members and their signal transduction machinery (receptors and Smad signal transducers) are functionally conserved between vertebrates and invertebrates. TG-interacting factor (TGIF) is a homeodomain-containing transcriptional corepressor of TGF-ß-dependent gene expression in mammals that is associated with holoprosencephaly in humans. Here we report a biochemical analysis of TGIF from zebra fish and Drosophila. Our study reveals an unprecedented role reversal between vertebrate and invertebrate TGIF proteins. Zebra fish TGIF, like its mammalian relative, interacts with general corepressors and represses TGF-ß-responsive gene expression. We identified a tandem duplication of TGIF genes in Drosophila. In contrast to vertebrate TGIFs, both Drosophila TGIFs strongly activate transcription. We also demonstrate that Drosophila TGIF proteins physically interact with both Mad and dSmad2, suggesting a role in Dpp and activin signaling. Thus, dTGIF may be the first transcription factor in the Drosophila activin pathway. Overall, our study suggests that assumptions about the functional equivalence of conserved proteins must be validated experimentally.

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