A C-terminally truncated form of β-catenin acts as a novel regulator of Wnt/β-catenin signaling in planarians

β-Catenin, the core element of the Wnt/β-catenin pathway, is a multifunctional and evolutionarily conserved protein which performs essential roles in a variety of developmental and homeostatic processes. Despite its crucial roles, the mechanisms that control its context-specific functions in time and space remain largely unknown. The Wnt/β-catenin pathway has been extensively studied in planarians, flatworms with the ability to regenerate and remodel the whole body, providing a ‘whole animal’ developmental framework to approach this question. Here we identify a C-terminally truncated β-catenin (β-catenin4), generated by gene duplication, that is required for planarian photoreceptor cell specification. Our results indicate that the role of β-catenin4 is to modulate the activity of β-catenin1, the planarian β-catenin involved in Wnt signal transduction in the nucleus, mediated by the transcription factor TCF-2. This inhibitory form of β-catenin, expressed in specific cell types, would provide a novel mechanism to modulate nuclear β-catenin signaling levels. Genomic searches and in vitro analysis suggest that the existence of a C-terminally truncated form of β-catenin could be an evolutionarily conserved mechanism to achieve a fine-tuned regulation of Wnt/β-catenin signaling in specific cellular contexts.
Author summary The Wnt signaling pathway is essential for proper intercellular communication in every developmental process since it controls basic cellular events as cell fate or proliferation. The key element of the Wnt signaling is β-catenin, which controls the transcription of multiple genes in the Wnt receiving cell. A main level of regulation of the Wnt/β-catenin signaling occurs in the cytoplasm, where β-catenin protein levels depend on the activity of the β-catenin destruction complex. However, once it reaches the nucleus, β-catenin transcriptional activity requires a fine-tuned regulation to enable the multiple context-specific responses that it performs. These nuclear mechanisms that regulate the Wnt/β-catenin signaling remain poorly understood. Here we report the existence of C-terminal truncated forms of β-catenin in planarians (β-cat3 and 4), which, in vitro, do not show transactivation activity and compete with the canonical planarian β-catenin (β-cat1), thus acting as competitor inhibitors. Functional analyses in planarians indicate that β-cat4 acts as a negative regulator of β-cat1 during planarian eye photoreceptor specification. We provide evidence to suggest that this novel mechanism for the regulation of nuclear β-catenin activity could be conserved across animal evolution.