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Published on: May 23, 2025
Canonical Wnt signaling negatively regulates platelet function
Brian M Steele1, Matthew T Harper, Iain C Macaulay
1Conway Institute, School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin 4, Ireland.
Abstract:
Wnts regulate important intracellular signaling events, and dysregulation of the Wnt pathway has been linked to human disease. Here, we uncover numerous Wnt canonical effectors in human platelets where Wnts, their receptors, and downstream signaling components have not been previously described. We demonstrate that the Wnt3a ligand inhibits platelet adhesion, activation, dense granule secretion, and aggregation. Wnt3a also altered platelet shape change and inhibited the activation of the small GTPase RhoA. In addition, we found the Wnt-beta-catenin signaling pathway to be functional in platelets. Finally, disruption of the Wnt Frizzled 6 receptor in the mouse resulted in a hyperactivatory platelet phenotype and a reduced sensitivity to Wnt3a. Taken together our studies reveal a novel functional role for Wnt signaling in regulating anucleate platelet function and may provide a tractable target for future antiplatelet therapy.
Insights
Wnt signaling, previously unknown in platelets, inhibits platelet activation and aggregation. This discovery reveals a new role for Wnt pathways in blood and suggests potential antiplatelet therapies.
Area of Science:
- Molecular Biology
- Hematology
- Cell Signaling
Background:
- Wnt signaling pathways regulate crucial intracellular events.
- Dysregulation of the Wnt pathway is implicated in various human diseases.
- The role of Wnt signaling in platelets has not been previously explored.
Purpose of the Study:
- To investigate the presence and function of Wnt signaling components in human platelets.
- To determine the effect of Wnt3a ligand on platelet function.
- To explore the Wnt-beta-catenin pathway's role in platelets.
Main Methods:
- Detection of Wnt pathway components in human platelets.
- Functional assays measuring platelet adhesion, activation, secretion, and aggregation.
- Assessment of Wnt3a effects on platelet shape change and RhoA activation.
- Analysis of platelet function in mice with disrupted Frizzled 6 receptor.
Main Results:
- Wnt3a ligand was found to inhibit platelet adhesion, activation, dense granule secretion, and aggregation.
- Wnt3a altered platelet shape change and inhibited RhoA activation.
- The Wnt-beta-catenin signaling pathway is functional in platelets.
- Disruption of the Frizzled 6 receptor in mice led to hyperactive platelets and reduced Wnt3a sensitivity.
Conclusions:
- Wnt signaling plays a novel functional role in regulating anucleate platelet function.
- Wnt pathway components are present and active in human platelets.
- This research may offer a new target for antiplatelet therapies.
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