Bejsovec Lab

Our goal is to understand how cells learn where they are in the body and how they use that positional information to make correct structures and patterns. We use fruitflies as a model system because their developmental pathways are very similar to humans, even though their body pattern is very different from ours. We focus on the Wnt pathway in particular, which generates pattern in flies and humans, and causes human cancers when it is not regulated properly.

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Here is a brief overview of how the pathway works, based on the work of many many labs: Wg pathway activity hinges on regulation of Arm, the fly beta-catenin homolog. In the absence of Wg signaling, Arm cytosolic levels are kept low by a set of proteins known collectively as the destruction complex. These proteins, which include the Axin and Apc scaffolding proteins and the serine-threonine kinase Zeste-white3 (Zw3)/GSK3b, phosphorylate Arm’s amino-terminal domain. This targets Arm for destruction via ubiquitination. When Wg binds to its receptors, Frizzled (Fz) and Arrow (LRP5/6 in vertebrates), this inactivates the destruction complex and stabilizes Arm. In the simplest view, Arm accumulation drives its interaction with Tcf, an HMG-box transcription factor, in the nucleus. Tcf binds DNA in the absence of Arm and represses Wg target genes in conjunction with Groucho (Gro/TLE1), a transcriptional co-repressor. When Arm binds to Tcf, it displaces Gro and recruits other proteins such as Legless (Lgs/BCL-9) and Pygopus (Pygo) to form a transcriptional activation complex that activates target gene expression.

For references, please see Bejsovec, A. (2013). Wingless/Wnt signaling in Drosophila: the pattern and the pathway. Molecular Reproduction and Development 80(11):882-94