Bejsovec Lab

Our work sought 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 used the fruitfly as a model system because its developmental pathways are very similar to humans, even though their body pattern is very different from ours. We focused on the Wnt pathway in particular, which generates pattern in flies and humans, and which causes human cancers when it is not regulated properly.

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. (A) In the absence of Wg signaling, the Apc and Axin scaffold presents Arm to Casein Kinase 1 (CK1) and Zeste white 3/Glycogen Synthase Kinase 3beta (Zw3/GSK) for phosphorylation. This targets Arm for ubiquitination and degradation by the proteasome. Tcf binds with the Gro transcriptional co-repressor at target genes, keeping their expression repressed. (B) Wg, concentrated at the cell surface by glycosaminoglycans on the glypican Dally, binds the Fz and Arrow receptors and causes them to cluster. This allows polymerization of Dsh and Axin at the plasma membrane, inactivating the kinase complex so that it cannot target Arm for destruction. Stabilized Arm translocates into the nucleus, binds to Tcf, and recruits the transcriptional activation complex, which includes Legless and Pygopus. This now turns on the expression of target genes. Structural features of proteins depicted here are based on data from (Wodarz and Nusse 1998, Annu Rev Cell Dev Biol 14: 59; Janda et al. 2012, Science 337:59).

For references, please see Bejsovec, A. (2018). Wingless Signaling: A Genetic Journey from Morphogenesis to Metastasis. Genetics 208: 1311-1336 (FlyBook chapter)