Project description
How genetic mutations rewire critical communication networks in cells
The non-canonical WNT/ROR pathway – an ancient cell communication network that guides how tissues form and develop – can cause rare genetic conditions such as Robinow syndrome, neurological disorders, and cancer metastasis when it malfunctions. Normally, this pathway relies on an adaptor protein called Dishevelled to assemble a signalling complex called a signalosome. However, the exact mechanisms of this network remain mysterious. Funded by the Marie Skłodowska-Curie Actions programme, the WNTRORinow project will investigate how disease-associated mutations change the signalosome’s molecular structure and disrupt cellular communication. Researchers will use CRISPR screening and proteomics to generate a detailed atlas of this network in health and disease. Project results could open new doors for targeted therapeutic discoveries.
Objective
WNT signalling pathways are evolutionarily conserved communication networks that control cell fate and tissue morphogenesis. While the canonical WNT/β-catenin pathway is well-studied, the non-canonical branch involving ROR receptors remains poorly understood, despite its critical role in development. Dysfunction of WNT/ROR signalling correlates with metastatic behaviour in cancer, neurological disorders and rare genetic diseases, most notably Robinow syndrome (RS). An essential step in this pathway is WNT ligand-induced activation of a receptor-bound signalling complex, termed the ‘signalosome’, assembled by the adaptor protein Dishevelled (DVL). However, the WNT/ROR signalosome component proteins and the mechanisms used to transduce its signals remain unclear.
In preliminary work in the host lab, I have identified a RS-associated DVL1 frameshift mutation that drives aberrant signalosome formation. How this variant alters the molecular composition of the signalosome and disrupts downstream signalling remains unknown. This MSCA project will uncover the mechanisms by which RS mutations deregulate WNT/ROR signalosome function, advancing our understanding of pathway activation.
In WP1, we will systematically characterise RS-associated DVL1-3 variants for their effects on signalosome assembly and signalling output using multiplexed WNT reporters and other tools, enabling the first comprehensive mechanistic analysis of these disease mutations. In WP2, we will map interactors involved in aberrant DVL assembly through proximity labelling proteomics and CRISPR-based screening, generating a high-confidence atlas of the WNT/ROR signalosome in health and disease. In WP3, we will dissect sequence motifs within the novel DVL C-termini that control assembly, revealing the molecular logic by which RS mutations rewire signalling dynamics.
By uncovering how WNT/ROR signalling is disrupted in rare disease, this work will pave the way for therapeutic exploration of this pathway.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences biochemistry biomolecules proteins proteomics
- natural sciences biological sciences genetics mutation
- medical and health sciences clinical medicine oncology
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA)
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships
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(opens in new window) HORIZON-MSCA-2025-PF
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CB2 1TN CAMBRIDGE
United Kingdom
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