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Cambridge Institute for Medical Research


Molecular mechanisms of Wnt signalling in health and disease

General audience summary:

Cells communicate by signal transduction pathways whereby secreted molecules bind to receptors on target cells to trigger intracellular responses. It is critical for our development and homeostasis that these signals are regulated and correctly interpreted. Not surprisingly, misregulation of signal transduction pathways is a leading cause of diseases, including rare genetic diseases, neurological disorders and cancer.
Our focus is on Wnt signalling, a collection of signalling pathways that regulate a diverse array of cellular processes including cell proliferation, differentiation, migration and polarity. We investigate how Wnts are able to selectively regulate either morphogenetic processes, namely migration and polarity, or cell fate decisions, such as proliferation.
We also investigate how misregulation of Wnt signalling, by abnormal expression and/or mutations cause rare genetic diseases, such as the skeletal dysplasia Robinow Syndrome and related disorders.
By better understanding how these pathways work at the molecular level, scientists will be able to devise better more targeted therapies.

COS7 cell transiently overexpressing DVL2-GFP (15hrs post-transfection). Scale bar = 10mm

Strategic CIMR Themes: Membrane trafficking, Organelle Biology, Rare genetic diseases, Neurological Diseases.

Funding: Wellcome Trust, The Blue-Sky collaboration (MRC and AstraZeneca)

Research Group Members:  Dr Gonzalo Beitia, Dr Miha Renko


Molecular mechanisms of Wnt signalling in health and disease.

Wnt signalling pathways orchestrate a multitude of fundamental biological processes, including cell fate determination and differentiation during embryonic development. The overwhelming majority of Wnt research to date has focussed on the canonical Wnt/b-catenin pathway, given its early identification as a driver of cancer. By contrast, the non-canonical Wnt/ROR pathway, which constitutes a core developmental pathway that controls tissue morphogenesis during development, remains poorly characterised.
Dysfunction of the Wnt/ROR pathway causes several rare genetic diseases and is implicated in neurological disorders and in driving the metastatic progression of many cancers. Therefore, defining the Wnt/ROR signalling pathway mechanistically is essential to develop better more targeted therapies and impact human health.
Our lab aims to transform our understanding of the crucial Wnt/ROR pathway, to elucidate how its misregulation drives developmental disease, and to determine how Wnt signals are specified to activate either canonical (Wnt/b-catenin) or non-canonical (Wnt/ROR) Wnt signalling branches at the molecular level.
Our starting focus is on Wnt signalosomes, dynamic multiprotein complexes which signify the branchpoint in Wnt signal specification but whose function and components require further elucidation. To achieve this, we will combine proteomics and biochemical/biophysical assays to identify novel signalling partners and define their direct interactions, as well as innovative cell-based functional assays to determine those that are essential for canonical and non-canonical signalling.



Key publications: 

Mieszczanek J#, Strutt H, Rutherford TJ, Strutt D, Bienz M*, Gammons MV*# (2022) The Dishevelled PDZ domain is selective for noncanonical Wnt signalling pathways. J Cell Sci 10.1242/jcs.259547.

Beitia GJ, Rutherford TJ, Freund SMV, Pelham HR, Bienz M, Gammons MV* (2021) Regulation of Dishevelled DEP domain swapping by conserved phosphorylation sites. PNAS 118(26):e2103258118.

Gammons MV*, Renko M*, Flack JE*, Mieszczanek J*, Bienz M (2020) Feedback control of Wnt signaling based on ultrastable histidine cluster co-aggregation between Naked/NKD and Axin. Elife. e59879.

Gammons MV*, Rutherford TJ, Steinhart Z, Angers S & Bienz M* (2016). Essential role of the Dishevelled DEP domain in a Wnt-dependent human cell-based complementation assay. J Cell Sci 129, 3892-3902.

Gammons MV*, Renko M, Johnson CM, Rutherford TJ & Bienz M* (2016). Wnt Signalosome Assembly by DEP Domain Swapping of Dishevelled. Molecular Cell 64, 92-104.

Principal Investigator
Dr Melissa Gammons

Contact Details
Takes PhD students
Available for consultancy


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