Extracellular regulation of BMP signalling in development and disease

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The Bone Morphogenetic Protein (BMP) pathway, one of the major cell signalling pathways, is important for development of nearly all human organs and tissues. In line with its central role in development, misregulation of BMP signalling leads to a variety of diseases including kidney, vascular and skeletal defects, as well as numerous cancers. Therefore, it is critical to understand the different ways in which the BMP pathway is regulated. The aim of this project is to use a multidisciplinary approach to understand the extracellular regulation of BMP signalling molecules, with particular focus on a BMP binding protein called Short Gastrulation (Sog). BMP regulation will be investigated in the Drosophila and Xenopus model organisms as they are tractable to manipulation and in the case of Drosophila a variety of genetic and genome engineering approaches. Firstly, a range of biophysical approaches will be used to investigate how Sog binds to BMPs and inhibits BMP activity. This analysis will allow various predictions to be made about the mechanisms of action of Sog in vivo. These predictions will be directly tested by introducing specific mutant forms of Sog into the Drosophila and Xenopus embryos and investigating how BMP signalling and development are affected. Overall, this project offers a unique opportunity to be trained in structural, molecular, developmental, genetic and genome engineering techniques. Moreover, a better understanding of how Sog functions in vivo will in the longer term be useful for the development of novel medical strategies to improve bone healing, and reduce atherosclerosis.ReferencesWinstanley, J., Sawala, A., Baldock, C. and Ashe, H.L. (2015). Synthetic enzyme-substrate tethering obviates the Tolloid-ECM interaction during Drosophila BMP gradient formation. eLife 4, e05508.Troilo, H., Zuk, A.V., Tunnicliffe, R.B., Wohl, A.P., Berry, R., Collins, R.F., Jowitt, T.A., Sengle, G. and Baldock, C. (2014). Nanoscale structure of the BMP antagonist chordin supports cooperative BMP binding. Proc Natl Acad Sci U S A. 111, 13063.Sawala, A., Sutcliffe, C. and Ashe, H.L. (2012). A multi-step molecular mechanism for BMP extracellular transport in the Drosophila embryo. PNAS 109, 11222. Berry R., Jowitt T.A., Ferrand J., Roessle M., Grossmann J.G., Canty-Laird E.G., Kammerer R.A., Kadler K.E. and Baldock C. (2009). Role of dimerization and substrate exclusion in the regulation of bone morphogenetic protein-1 and mammalian tolloid. Proc Natl Acad Sci 106, 8561-6.Wang, X., Harris, R.E., Bayston, L.J. and Ashe, H.L. (2008). Type IV collagens regulate BMP signalling in Drosophila. Nature 454, 72-78.