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Multiple mechanisms for Wnt11-mediated repression of the canonical Wnt signaling pathway
Peter Maye1, Jie Zheng, Lin Li
1Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, Connecticut 06030, USA.
Abstract:
The effect of a noncanonical Wnt, Wnt11, on canonical Wnt signaling stimulated by Wnt1 and activated forms of LRP5 (low density lipoprotein receptor-related protein-5), Dishevelled1 (Dvl1), and beta-catenin was examined in NIH3T3 cells and P19 embryonic carcinoma cells. Wnt11 repressed Wnt1-mediated activation of LEF-1 reporter activity in both cell lines. However, Wnt11 was unable to inhibit canonical signaling activated by LRP5, Dvl1, or beta-catenin in NIH3T3 cells, although it could in P19 cells. In addition, Wnt11-mediated inhibition of canonical signaling in NIH3T3 cells is ligand-specific; Wnt11 could effectively repress canonical signaling activated by Wnt1, Wnt3, or Wnt3a but not by Wnt7a or Wnt7b. Co-culture experiments with NIH3T3 cells showed that the co-expression of Wnt11 with Wnt1 was not an essential requirement for the inhibition, suggesting receptor competition as a possible mechanism. Moreover, in both cell types, elevation of intracellular Ca(2+) levels, which can result from Wnt11 treatment, led to the inhibition of canonical signaling. This result suggests that Wnt11 might not be able to signal in NIH3T3. Furthermore, P19 cells were found to express both endogenous canonical Wnts and Wnt11. Knockdown of Wnt11 expression using siRNA resulted in increased LEF-1 reporter activity, thus indicating that Wnt11-mediated suppression of canonical signaling exists in vivo.
Insights
Noncanonical Wnt11 suppresses canonical Wnt signaling in a cell-specific manner, potentially through receptor competition or calcium signaling, and this Wnt11-mediated suppression is observed in vivo.
Area of Science:
- Cell biology
- Molecular signaling
- Developmental biology
Background:
- Canonical Wnt signaling is crucial for embryonic development and cellular processes.
- Noncanonical Wnt ligands, like Wnt11, can modulate canonical Wnt pathways.
- Understanding Wnt11's role in canonical Wnt signaling is essential for deciphering developmental mechanisms.
Purpose of the Study:
- To investigate the effect of noncanonical Wnt11 on canonical Wnt signaling.
- To determine the cell-type specificity and molecular mechanisms of Wnt11's inhibitory action.
- To assess the in vivo relevance of Wnt11-mediated suppression of canonical Wnt signaling.
Main Methods:
- Utilized NIH3T3 and P19 cell lines to study Wnt signaling.
- Examined Wnt11's effect on reporter gene activity (LEF-1) activated by Wnt1 and downstream components (LRP5, Dvl1, beta-catenin).
- Performed co-culture experiments, measured intracellular calcium levels, and used siRNA for Wnt11 knockdown.
Main Results:
- Wnt11 repressed Wnt1-mediated canonical signaling in both cell lines.
- Wnt11 inhibited signaling activated by downstream components in P19 cells but not NIH3T3 cells.
- Wnt11's inhibitory effect was ligand-specific and suggested receptor competition.
- Elevated intracellular calcium levels correlated with Wnt11-induced inhibition, indicating potential signaling defects in NIH3T3 cells.
- Wnt11 knockdown in P19 cells increased canonical signaling, confirming in vivo suppression.
Conclusions:
- Wnt11 exhibits cell-specific inhibitory effects on canonical Wnt signaling.
- Mechanisms may involve receptor competition and calcium signaling.
- Wnt11 plays a role in suppressing canonical Wnt signaling in vivo.
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