Loss of the noncanonical Wnt pathway boosts β-catenin levels.

Members of the Wnt family of secreted signaling proteins control a wide range of developmental and pathological processes, with each Wnt protein signaling through either the “canonical” or “noncanonical” pathway. Two papers in this issue (and a Comment on page 753) now bring these two pathways together, showing that the noncanonical can directly antagonize the canonical to regulate signals critical for vertebrate body axis determination, limb development, and possibly oncogenesis.

The canonical Wnt pathway stabilizes the signaling protein β-catenin against degradation, whereas the noncanonical pathway has been considered largely β-catenin independent, operating instead through a network of calcium-dependent intermediates.

Westfall et al. (page 889) identified the noncanonical Wnt family members in zebrafish and found that a loss of function in one of them, Wnt-5, leads to an increase in β-catenin activity and activation of genes downstream of the canonical pathway. When Wnt-5 is absent from both the mother and the zygote, embryos become hyperdorsalized, showing that this noncanonical Wnt signal is required for proper embryonic axis formation.

Topol et al. (page 899) found that in mice the loss of a homologous gene, Wnt-5a, leads to an increase in canonical Wnt signaling in the distal limb bud. The unchecked canonical signal then inhibits chondrogenesis, causing defects in limb development. Analysis of cultured mammalian cells confirms that Wnt-5a signaling decreases β-catenin activity.

In both systems, the noncanonical signal increases β-catenin degradation, thereby inhibiting the canonical pathway and allowing development to proceed normally. Topol et al. also show that this activity of Wnt-5a requires APC, suggesting that Wnt-5a could also be an oncosuppressor. The authors are now trying to determine whether Wnt-5a is mutated in any human tumors. Meanwhile, Westfall et al. hope to use the zebrafish model to identify intermediates in the noncanonical Wnt pathway. ▪