Understanding non-canonical Wnt/ROR signalling – a hub for rare and common disease pathogenesis

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 has focussed on the canonical Wnt/b-catenin pathway. 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. My vision is to transform our understanding of the crucial Wnt/ROR pathway and elucidate how its misregulation drives developmental disease. My starting focus is on Wnt/ROR signalosomes, which are dynamic multiprotein complexes whose function and components require elucidation. I will use wildtype and disease-associated mutants in proximity labelling proteomic assays to systemically identify novel Wnt/ROR signalling partners. This will be combined with biochemical assays to define their direct interactions and innovative cell-based functional assays to determine those that are essential for signalling. I will determine: (1) Wnt/ROR signalosome components (2) ROR-receptor pseudokinase signalling mechanisms and (3) uncover how Wnt/ROR abnormalities cause developmental diseases.