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A developmental conundrum: a stabilized form of beta-catenin lacking the transcriptional activation domain triggers features of hair cell fate in epidermal cells and epidermal cell fate in hair follicle cells.

ABSTRACT: Wnt signaling orchestrates morphogenetic processes in which changes in gene expression are associated with dramatic changes in cell organization within developing tissue/organs. Upon signaling, excess beta-catenin not utilized at cell-cell junctions becomes stabilized, where it can provide the transcriptional activating domain for Lef/Tcf DNA binding proteins. In skin epithelium, forced stabilization of beta-catenin in epidermis promotes hair follicle morphogenesis, whereas conditional removal of beta-catenin in hair progenitor cells specifies an epidermal fate. We now report that a single protein, a stabilized version of beta-catenin lacking the COOH-terminal transactivation domain, acts in epidermis to promote hair fates and in hair cells to promote epidermal fate. This reveals fundamental differences in ways that epidermal and hair cells naturally respond to beta-catenin signaling. In exploring the phenotype, we uncovered mechanistic insights into the complexities of Lef1/Tcf/beta-catenin signaling. Importantly, how a cell will respond to the transgene product, where it will be localized, and whether it can lead to activation of endogenous beta-catenin/Tcf/Lef complexes is specifically tailored to skin stem cells, their particular lineage and their relative stage of differentiation. Finally, by varying the level of beta-catenin signaling during a cell fate program, the skin cell appears to be pliable, switching fates multiple times.

SUBMITTER: DasGupta R

PROVIDER: S-EPMC2173126 | biostudies-other | 2002 Jul

REPOSITORIES: biostudies-other

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Project description:Rationale: β-catenin signaling controls multiple fibroblast subsets, with its overactivity promoting the differentiation of hair follicle dermal stem cells (hfDSCs) and the hyperactivation of interfollicular fibroblasts. Understanding the concept of hfDSC activation and modulation offers hope towards the therapeutic armamentarium in dermatology and related comorbidities, as well as their potential applications in gerontology (the study of physiological aging). Having a comprehensive understanding in this stochastic process could also further yield important, novel insights into the molecular basis of skin aging to improve lifespan and preventing aging-related diseases. Methods: A new CD34CrePGR mouse line was generated. Through fate-tracing models and a series of β-catenin genetic experiments, our study depicts how the wound environment increases phosphorylated β-catenin in hfDSCs and facilitates their differentiation into dermal papilla (DP) and dermal sheath (DS). In mice carrying hfDSC-specific activated allele of β-catenin, hfDSCs accelerated their differentiation into DP cells. Results: Notably, with β-catenin stabilization in CD34-expressing cells and potential activation of canonical Wnt signaling, the mutant mice showed a brief increase of hair density in the short term, but over time leads to a senescence phenotype developing premature canities and thinning [hair follicle (HF) miniaturization]. Conclusion: β-catenin signaling drove HF senescence by accelerating differentiation of CD34+ hfDSCs, resulting in phenotypes attributable to the differentiation of the hfDSCs into DP cells and the loss of their stem cell potential. Therefore, our study reveals that the regulation of β-catenin signaling in hfDSCs may potentially become an important subject for future exploration in development of clinically effective therapies for hair loss treatment and an excellent model for revealing new therapeutic approaches to reverse aging or retarding the development of alopecia.

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A developmental conundrum: a stabilized form of beta-catenin lacking the transcriptional activation domain triggers features of hair cell fate in epidermal cells and epidermal cell fate in hair follicle cells.

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