TGF-Bs are secreted polypeptides that play important roles in controlling growth and development in animals by regulating gene expression in responding cells. It is thought that they do this directly through activation of intracellular proteins of the Smad family, but recent results have identified an alternative, indirect mechanism by which one TGF-B, Dpp in Drosophila, can control target gene expression: through negative regulation of a repressor of these targets encoded by the brinker (brk) gene. The Brk protein is nuclear and has a putative helix-turn-helix DNA binding motif, suggesting it is a DNA binding protein and may repress transcription directly. Dpp downregulates Brk expression and this relief from repression appears sufficient to allow expression of Dpp targets. The primary aim of the present project is to understand how expression of Dpp targets is regulated by Brk. This will be studied in the developing wing of Drosophila where Dpp controls patterning along the anteroposterior axis by acting as a graded morphogen.
The specific aims are as follows. (1) To position Brk in. the Dpp signaling pathway. Preliminary results place Brk downstream of Mad, but this must be confirmed and does not rule out direct interactions with other components of this pathway. (2) To determine how Dpp signaling regulates brk expression. In general, Smads function to activate gene expression so the pathway from Mad to brk repression is unclear. (3) To determine the function of the Brk protein, primarily to show if it is a DNA binding protein. (4) To analyze the developmental significance of the Brk mechanism. The gradient of Dpp along the A/P axis in the wing is transduced into a complementary gradient of Brk expression which may provide positional information in this system, i.e. different Brk concentrations may produce different responses. TGF-B signal transduction mechanisms are highly conserved suggesting the indirect Brk-mediated mechanism will not be unique to flies. Disrupting TGF-B signaling can have profound effects in humans, resulting in different types of cancer or even congenital abnormalities. Consequently, the present research should have direct relevance to our understanding of how defects in TGF-B signaling can lead to disease.
| Wehn, Amy; Campbell, Gerard (2006) Genetic interactions among scribbler, Atrophin and groucho in Drosophila uncover links in transcriptional repression. Genetics 173:849-61 |
| Moser, Melissa; Campbell, Gerard (2005) Generating and interpreting the Brinker gradient in the Drosophila wing. Dev Biol 286:647-58 |
| Winter, Stephanie E; Campbell, Gerard (2004) Repression of Dpp targets in the Drosophila wing by Brinker. Development 131:6071-81 |
