Regulation of morphogen signaling at the plasma membrane: Novel components and interactions in the formation of graded BMP signaling in Drosophila wing imaginal discs
Final Report Abstract
Gradients of signaling activity (morphogen signaling) are important for organ growth and patterning. The present study has focused on the BMP signaling in the Drosophila wing imaginal disc, a well-established paradigm for the investigation of morphogen signaling. We specifically focused on mechanisms that affect gradient formation by acting at the level of the plasma membrane of the wing disc epithelium. As a basis for this analysis, we have generated a comprehensive collection of endogenously tagged components of the system, including the regulator Pent, the receptors Tkv, Put, Sax and Wit and the co-receptors Dally and Dally-like protein. The generated flies allow monitoring the tissue and subcellular distribution of the individual components at physiological spatio-temporal expression patterns in the larval wing disc epithelium. Since the use of these chimeric proteins is not restricted to the wing, we anticipate that our collection of functional, chimeric proteins will facilitate studies on BMP signaling in multiple contexts. Using these tools, we could provide insights into the molecular activity of Pent, a protein that is essential for proper BMP signaling gradient formation. Specifically we could show that Pent regulates BMP signaling by adjusting levels of glypicans. Specifically, Pent was found to bind to glypicans and to induce their internalization and membrane-depletion thus regulating the ability of the epithelial cells to recruit and trap Dpp, the main BMP ligand of the system. We could also demonstrate a requirement of Pent in other processes that depend on glypican activity, such as Wingless signaling. In addition to the work on Pent, we have investigated the role of two potential regulators of BMP signaling, the transmembrane proteins Lambik (Lbk) and G5639. However, our genetic studies could not provide support for a role of these proteins in the regulation of the BMP signaling gradient. To further identify components that might affect gradient formation at the plasma membrane, we performed an in vivo, RNA-based screen targeting secreted and transmembrane proteins. We have identified 53 candidates that are currently being verified for a participation in wing development and BMP signaling gradient establishment.
Publications
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Regulation of BMP Signaling Gradients in Drosophila, PhD-Thesis, 2013
Milica Jevtic
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The Drosophila BMPRII, Wishful thinking, is required for eggshell patterning. Developmental Biology, 375, 45-53, 2013
Marnion R., Jevtic M., Springhorn A., Pyrowolakis G. and Yakoby N
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Dpp/BMP signaling in flies; from the molecules to the biology. Semin Cell Dev Biol, 32C, 128-136, 2014
Hamaratoglu F, Affolter M, Pyrowolakis G
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Functions and Gene Regulatory Mechanisms of BMP Signaling in Drosophila, PhD-Thesis, 2014
Alexander Springhorn
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Pentagone fine-tunes glypicans to regulate multiple signaling pathways. Elife, 5 e13301, 2016
Norman M, Vuilleumier R, Springhorn A, Gawlik J, Pyrowolakis G
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The protein kinase LKB1 negatively regulates bone morphogenetic protein receptor signaling. Oncotarget, 7(2), 1120-43, 2016
Raja E, Tzavlaki K, Vuilleumier R, Edlund K, Zieba A, Morén, Watanabe Y, Voytyuk I, Botling J, Söderberg O, Micke P, Pyrowolakis G, Heldin CH, Moustakas A
