Extracellular Regulation of BMP signaling in Development and Disease

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Bone Morphogenic Protein (BMP) signaling is a key pathway in the development of vertebrates and invertebrates, as well as into adulthood. As such, misregulation of BMP signaling can lead to a wide variety of diseases, including skeletal defects and various cancers. A key way in which BMP signaling is regulated is in the extracellular environment via a key protein, Sog, employed at many developmental stages. The regulation of BMP by Sog is modulated by a set of proteins, including Twisted Gastrulation (Tsg). Tsg can enhance Sog inhibition of BMP by promoting formation of a ternary Sog-Tsg-BMP complex which blocks BMP binding its target receptor and therefore signaling. However, Tsg also displays pro-BMP signaling activity in different contexts. The aim of this project is to further investigate how Sog and Tsg are able to regulate BMP signaling in the extracellular environment. Given the conserved nature of the pathway, BMP regulation will be investigated in the model organism Drosophila melanogaster. Structural characterization of the Sog-BMP and Sog-BMP-Tsg complexes will be achieved using Small Angle Xray Scattering and Cryo-Electron Microscopy. Moreover, live imaging will be used to visualize and follow the formation and fate of Sog and Tsg complexes during embryonic development. Finally, CRISPR-mediated genome editing will allow targeted mutagenesis to key residues to disturb interactions identified by the structural characterization of the complexes and the effect of such disturbances on the protein localization, function and embryonic patterning will be determined. Through this project, a better understanding of the molecular level regulation BMP signaling will aid not just in the academic understanding of early developmental regulation, but also in the design of novel reagents to inhibit or enhance BMP signaling. This represents a major therapeutic goal.