Wnt/β-catenin’s regulatory role in embryonic stem cell pluripotency and differentiation

Abstract

Stem cells need to tightly regulate the switch between self-renewal and differentiation. Several external signaling pathways contribute to this regulation, together with the internal regulatory gene network. One of the signaling pathways that promotes embryonic stem (ES) cell self-renewal is the Wnt/β-catenin pathway. However, Wnt signaling is also known to induce differentiation of ES cells. This raises the question of how it is possible that the same signaling pathway promotes both pluripotency and differentiation and how the Wnt pathway cooperates with the internal transcriptional circuitry to regulate these processes. Here, an attempt will be made to address these questions; this thesis will discuss the different reports that show a role of Wnt signaling in promoting either differentiation or pluripotency. I will describe how the Wnt/β-catenin pathway interplays with the regulatory gene network of pluripotency in ES cells and finally I will try to explain how it is possible that Wnt signaling plays two distinct roles in the regulation of these processes. There have been several hypotheses proposed of how the Wnt/β-catenin pathway promotes pluripotency. The first suggests that β-catenin directly regulates the internal regulatory gene network of pluripotency in ES cells, which consists of OCT4, SOX2 and NANOG. TCF3 acts as repressor of this regulatory circuitry and β-catenin can relieve this repression, promoting ES cell pluripotency. The second hypothesizes that a direct interaction between OCT4 and β-catenin promotes pluripotency as well. The last hypothesis proposes a role for β-catenin/TCF mediated transcription in maintaining ES cell pluripotency. Aside from promoting pluripotency, Wnt/β-catenin signaling has been shown to induce differentiation. Whether Wnt/β-catenin signaling promotes ES cell pluripotency or differentiation might be a result of differential co-activator usage. Two histone acetyltransferases CBP and p300 could act as co-activators of β-catenin mediated transcription; CBP together with β-catenin promotes pluripotency, whereas p300 as a co-activator induces differentiation. Other external signaling pathways may determine the choice of co-activator usage and hence influence the outcome of Wnt/β-catenin signaling.