Abstract
Cells have developed numerous adaptation mechanisms to external cues by controlling signaling-pathway activity, both qualitatively and quantitatively. The Wnt/β-catenin pathway is a highly conserved signaling pathway involved in many biological processes, including cell proliferation, differentiation, somatic cell reprogramming, development, and cancer. The activity of the Wnt/β-catenin pathway and the temporal dynamics of its effector β-catenin are tightly controlled by complex regulations. The latter encompass feedback loops within the pathway (e.g., a negative feedback loop involving Axin2, a β-catenin transcriptional target) and crosstalk interactions with other signaling pathways. Here, we provide a review shedding light on the coupling between Wnt/β-catenin activation levels and fluctuations across processes and cellular systems; in particular, we focus on development, in vitro pluripotency maintenance, and cancer. Possible mechanisms originating Wnt/β-catenin dynamic behaviors and consequently driving different cellular responses are also reviewed, and new avenues for future research are suggested.
Highlights
Wnt proteins are key mediators of cell specification and patterning in development, adult tissue homeostasis, and stemness [1]
It is involved in cell–cell adhesion through interaction with the E-cadherin cell-adhesion complex and the microtubule network [27,28,29,30,31,32,33,34], and can trigger gene expression in complex with T-cell transcription factor/lymphocyte enhancer factor (TCF/LEF) family members [35,36,37,38,39,40,41,42,43,44]
Increased β-catenin expression was shown to force the differentiation of the embryonic ectoderm into hair follicles and promote de novo hair-follicle induction in adult skin; on the other hand, β-catenin depletion led to reduced proliferation of epithelial cells and premature catagen [94]
Summary
Wnt proteins are key mediators of cell specification and patterning in development, adult tissue homeostasis, and stemness [1]. Increased β-catenin expression was shown to force the differentiation of the embryonic ectoderm into hair follicles and promote de novo hair-follicle induction in adult skin; on the other hand, β-catenin depletion led to reduced proliferation of epithelial cells and premature catagen (i.e. regression phase prior to telogen) [94] These observations indicate a temporal “wave” of β-catenin, with high/low levels in the initial/proliferative (and committed) phases, respectively [94]. To tip such balance between proliferation and differentiation [95,96], members of the Wnt family are dynamically expressed in developing hair follicles and skin, and the β-catenin protein itself shows dynamic changes in both accumulation levels and subcellular localization [97,98,99,100,101,102].
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