Wnt Signaling in Stem Cells

Abstract

Wnt signaling pathways play divergent roles during development, normal homeostasis and disease. Wnt signaling is also critically important in stem cell biology. It has been demonstrated to be involved in both the proliferation and differentiation of stem and progenitor populations. Wnt/β-catenin signaling also plays a critical role in lineage decision/commitment. These dramatically different outcomes upon activation of the Wnt signaling cascade has fueled enormous controversy concerning the role of Wnt signaling in maintenance of potency and induction of differentiation. Tight regulation and controlled coordination of the Wnt signaling cascade is required to maintain the balance between proliferation and differentiation. The diverse and titrated responses that result from the activation of the Wnt signaling pathway however begs the question of how the Wnt signaling network integrates the various inputs that a cell receives to elicit the correct and coordinated responses.

Until recently, a rationale for the dichotomous behavior of Wnt/beta-catenin signaling in controlling both proliferation and differentiation has been unclear. Using a selective antagonist of the CBP/beta-catenin interaction that we identified using a chemical genomic approach, we have developed a model to explain the divergent activities of Wnt/beta-catenin signaling. Our model highlights the distinct and non-redundant roles of the coactivators CBP and p300 in the Wnt/beta-catenin signaling cascade. The critical feature of the model is that CBP/catenin mediated transcription is critical for proliferation and stem cell/progenitor cell maintenance; whereas p300/catenin mediated transcription leads to the differentiation program. The ‘decision’ to partner with either CBP or p300 is the first key decision point to initiate either a proliferative or a differentiative program, respectively. This initiation of proliferation or differentiation is followed by additional epigenetic modifications as well as the recruitment of additional transcription factors for both subsequent expansion of transient amplifying populations and/or lineage commitment.

The ultimate decision for a cell to either initiate differentiation, or not, must be integrated and funneled down into a decision point. We propose that essentially all cellular information – i.e. from other signaling pathways, nutrient levels, etc. – is funneled down into a choice of coactivators usage, either CBP or p300, by their interacting partner beta-catenin (or catenin-like molecules in the absence of beta-catenin) to make the critical decision to either remain quiescent, or once entering cycle to proliferate without differentiation or to initiate the differentiation process.