Dissecting and manipulating regulatory feedback circuitry in Drosophila BMP morphogen signaling

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Tissue growth and patterning during animal development is critically controlled by morphogens, secreted signaling molecules that establish gradients of signaling activity. The importance of morphogen signaling is reflected by the multitude of regulatory mechanisms that control the range, and the shape of the signaling gradient. Central amongst such mechanisms are regulatory feedback loops that couple signaling responses to gradient establishment and maintenance and have been suggested to equip morphogen signaling with precision, robustness and the ability to scale with tissue growth in a given context. The proposed project focuses on BMP (Bone Morrphogenetic Protein) morphogen signaling and aims at addressing how regulatory feedback circuitries might be rewired to produce differential signaling profiles and output in different contexts. As a model we will focus on two dorsal appendages of Drosophila, the wing and the haltere, which drastically differ in size and form despite sharing developmental history and dependence on a gradient of Dpp (Decapentaplegic, a Drosophila BMP) for growth and differentiation. Previous work has established that differences in the Dpp gradient critically contribute to size differences between the two organs. Genetic studies also suggested that the differences in BMP signaling are partly due to differences in BMP-dependent regulation of the BMP-receptor Thickveins (Tkv). In the larval wing, BMP signaling represses tkv transcription which allows for efficient ligand spreading and establishment of a long-range BMP signaling gradient. In contrast, in the larval haltere precursor, BMP-dependent repression of tkv is blocked by the homeotic Protein Ultrabithorax (Ubx) and high Tkv levels trap Dpp resulting in a short-range and compacted BMP signaling gradient. In this project, we wish to understand and challenge the mechanisms that account for the differences in this regulatory feedback. Specifically, we wish to understand the molecular mechanisms that couple Tkv production to BMP signaling in the wing and how Ubx integrates with such mechanisms to uncouple feedback regulation during haltere development. We wish to reach a level of understanding that will allow us, in a second part of the project, to alter the properties of this feedback-loop and assess effects of such manipulations at both the level of signaling activity (profile of the Dpp gradient) and signaling output (organ size) in vivo. Our studies will provide insights in the mechanisms by which regulatory feedback circuitries can be rewired to adapt signaling activity to tissue-specific 'demands'.