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Cell Aggregation Assays to Evaluate the Binding of the Drosophila Notch with Trans-Ligands and its Inhibition by Cis-Ligands
Published on: January 2, 2018
Dishevelled limits Notch signalling through inhibition of CSL
Giovanna M Collu1, Ana Hidalgo-Sastre, Ahmet Acar
1Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK. giovanna.collu@mssm.edu
Abstract:
Notch and Wnt are highly conserved signalling pathways that are used repeatedly throughout animal development to generate a diverse array of cell types. However, they often have opposing effects on cell-fate decisions with each pathway promoting an alternate outcome. Commonly, a cell receiving both signals exhibits only Wnt pathway activity. This suggests that Wnt inhibits Notch activity to promote a Wnt-ON/Notch-OFF output; but what might underpin this Notch regulation is not understood. Here, we show that Wnt acts via Dishevelled to inhibit Notch signalling, and that this crosstalk regulates cell-fate specification in vivo during Xenopus development. Mechanistically, Dishevelled binds and directly inhibits CSL transcription factors downstream of Notch receptors, reducing their activity. Furthermore, our data suggest that this crosstalk mechanism is conserved between vertebrate and invertebrate homologues. Thus, we identify a dual function for Dishevelled as an inhibitor of Notch signalling and an activator of the Wnt pathway that sharpens the distinction between opposing Wnt and Notch responses, allowing for robust cell-fate decisions.
Insights
Wnt signaling inhibits Notch signaling through Dishevelled, which directly blocks CSL transcription factors. This crosstalk ensures robust cell-fate decisions during development.
Area of Science:
- Developmental Biology
- Molecular Biology
- Cell Signaling
Background:
- Notch and Wnt are conserved signaling pathways crucial for animal development.
- These pathways often have opposing roles in cell-fate determination.
- Wnt signaling typically dominates when both pathways are active, suggesting Wnt inhibits Notch, but the mechanism is unknown.
Purpose of the Study:
- To elucidate the molecular mechanism by which Wnt signaling inhibits Notch signaling.
- To investigate the role of this crosstalk in cell-fate specification during Xenopus development.
- To identify the key molecules involved in mediating Wnt-induced Notch inhibition.
Main Methods:
- Utilized Xenopus laevis as an in vivo model system.
- Investigated protein-protein interactions between Wnt pathway components and Notch signaling effectors.
- Assessed the impact of Dishevelled on CSL transcription factor activity downstream of Notch receptors.
Main Results:
- Demonstrated that Wnt signaling inhibits Notch signaling via Dishevelled.
- Showed that Dishevelled directly binds to and inhibits CSL transcription factors.
- Confirmed that this Wnt-Dishevelled-CSL interaction regulates cell-fate specification in vivo.
- Provided evidence for the conservation of this crosstalk mechanism across species.
Conclusions:
- Discovered a novel mechanism where Dishevelled acts as a direct inhibitor of Notch signaling by targeting CSL transcription factors.
- Identified a dual role for Dishevelled in activating Wnt and inhibiting Notch signaling.
- Established that this crosstalk sharpens opposing pathway responses, enabling robust cell-fate decisions.
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