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Updated: May 28, 2026
Modeling Paracrine Noncanonical Wnt Signaling In Vitro
Published on: December 10, 2021
Dickkopf1--a new player in modelling the Wnt pathway
Lykke Pedersen1, Mogens Høgh Jensen, Sandeep Krishna
1Center for Models of Life, Niels Bohr Institute, Copenhagen, Denmark. lykkep@nbi.dk
Abstract:
The Wnt signaling pathway transducing the stabilization of β-catenin is essential for metazoan embryo development and is misregulated in many diseases such as cancers. In recent years models have been proposed for the Wnt signaling pathway during the segmentation process in developing embryos. Many of these include negative feedback loops where Axin2 plays a key role. However, Axin2 null mice show no segmentation phenotype. We therefore propose a new model where the negative feedback involves Dkk1 rather than Axin2. We show that this model can exhibit the same type of oscillations as the previous models with Axin2 and as observed in experiments. We show that a spatial Wnt gradient can consistently convert this temporal periodicity into the spatial periodicity of somites, provided the oscillations in new cells arising in the presomitic mesoderm are synchronized with the oscillations of older cells. We further investigate the hypothesis that a change in the Wnt level in the tail bud during the later stages of somitogenesis can lengthen the time period of the oscillations and hence the size and separation of the later somites.
Insights
A new model proposes Dkk1, not Axin2, mediates negative feedback in Wnt signaling during embryonic development. This model explains somite formation and periodicity, offering insights into developmental biology and disease.
Area of Science:
- Developmental Biology
- Molecular Biology
- Systems Biology
Background:
- The Wnt signaling pathway, crucial for metazoan development, involves β-catenin stabilization and is implicated in diseases like cancer.
- Existing models of Wnt signaling in embryonic segmentation often feature Axin2 in negative feedback loops.
- Axin2 null mice do not exhibit segmentation defects, suggesting alternative feedback mechanisms.
Purpose of the Study:
- To propose and validate a new model for Wnt signaling during embryonic segmentation.
- To investigate the role of Dkk1 in negative feedback loops, replacing Axin2.
- To explore how temporal oscillations in Wnt signaling translate to spatial patterns of somite formation.
Main Methods:
- Computational modeling of the Wnt signaling pathway.
- Analysis of negative feedback loops involving Dkk1.
- Investigating the conversion of temporal oscillations to spatial periodicity via Wnt gradients.
- Simulating the effect of Wnt level changes on oscillation period.
Main Results:
- The proposed Dkk1-mediated negative feedback model replicates observed Wnt signaling oscillations.
- The model demonstrates how a spatial Wnt gradient can generate somite periodicity from temporal oscillations.
- Synchronization of cell oscillations in the presomitic mesoderm is shown to be critical for spatial pattern formation.
- Altered Wnt levels in the tail bud can modulate oscillation period, affecting somite size and spacing.
Conclusions:
- Dkk1 is a plausible key regulator in the negative feedback loop of Wnt signaling during somitogenesis.
- The interplay between temporal oscillations, spatial Wnt gradients, and cell synchronization governs somite formation.
- Modulation of Wnt levels offers a mechanism for regulating somite characteristics in later developmental stages.
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