Pygo2 regulates β-catenin-induced activation of hair follicle stem/progenitor cells and skin hyperplasia (original) (raw)
Related papers
Cell Stem Cell, 2013
Wnt/b-catenin signaling is a central regulator of adult stem cells. Variable sensitivity of Wnt reporter transgenes, b-catenin's dual roles in adhesion and signaling, and hair follicle degradation and inflammation resulting from broad deletion of epithelial b-catenin have precluded clear understanding of Wnt/b-catenin's functions in adult skin stem cells. By inducibly deleting b-catenin globally in skin epithelia, only in hair follicle stem cells, or only in interfollicular epidermis and comparing the phenotypes with those caused by ectopic expression of the Wnt/b-catenin inhibitor Dkk1, we show that this pathway is necessary for hair follicle stem cell proliferation. However, b-catenin is not required within hair follicle stem cells for their maintenance, and follicles resume proliferating after ectopic Dkk1 has been removed, indicating persistence of functional progenitors. We further unexpectedly discovered a broader role for Wnt/b-catenin signaling in contributing to progenitor cell proliferation in nonhairy epithelia and interfollicular epidermis under homeostatic, but not inflammatory, conditions.
Plastic and Aesthetic Research, 2016
Aim: The differentiation of hair follicle stem cells (HFSCs) into hair follicle cells has potential clinical applications for cutaneous burns. However, the mechanisms regulating the differentiation of HFSCs into hair follicular papilla or epidermal cells are currently not clear. This study investigated the role of the Wnt/β-catenin pathway and its crosstalk with other signaling components during this differentiation process. Methods: Lithium chloride (LiCl, 10 mmol/L) and keratinocyte growth factor (KGF, 10 µg/L) were used to induce HFSC differentiation, validated by immunofluorescence analysis. The mRNA expression of β-catenin, adenomatous polyposis coli, glycogen synthase kinase-3β (GSK-3β), axin, and lymphoid enhancer factor-1 after 3, 5, 7, and 9 days were measured to evaluate the role of the Wnt/β-catenin pathway. Results: During LiCl-induced HFSC differentiation into hair follicle cells, the Wnt/ β-catenin signaling pathway was activated and the expression of GSK-3β, a vital component of the degradation compound, was inhibited. This led to increased cytoplasmic β-catenin expression, nuclear translocation, and subsequent target gene transcription. By contrast, KGF induced the differentiation of HFSCs into epidermal cells and did not affect the expression of β-catenin. This data indicates that LiCl and KGF distinctly regulate the differentiation of HFSCs into hair follicle and epidermal cells, respectively. Furthermore, the Wnt/β-catenin signaling pathway is predominantly involved in hair follicle differentiation. Conclusion: these results demonstrate that LiCl can be used to differentiate HFSCs into hair follicle cells in vitro, which has important therapeutic applications for treating patients with cutaneous damage. MJ. Modulation of Wnt/β-catenin signaling affects the directional differentiation of hair follicle stem cells. Plast Aesthet Res 2016;3:39-46.
β-Catenin Controls Hair Follicle Morphogenesis and Stem Cell Differentiation in the Skin
Cell, 2001
sion of the hair follicle drags the dermal papilla upward 1 Max-Delbrueck-Center for Molecular Medicine into the dermis toward the bulge. At the initiation of a Robert-Roessle-Strasse 10 new anagen stage, follicular stem cells appear to re-13092 Berlin spond to signals from the dermal papilla, and give rise Germany to the next generation of proliferating matrix cells. The 2 Department of Dermatology bulge also delivers progenitor cells to the basal layer of University of Pennsylvania the epidermis. Follicular stem cells and the different 422 Curie Boulevard keratinocyte lineages express distinct proteins that can Philadelphia, Pennsylvania be used to distinguish the different cell types (Heid et al., 1988; Fuchs, 1995; Langbein et al., 1999). Little is known about how stem cells of the skin are maintained Summary and how their commitment to different keratinocyte lineages is controlled. Recently, the P53 homolog P63 has -Catenin is an essential molecule in Wnt/wingless been implicated in the regenerative aspect of stem cell signaling, which controls decisive steps in embryodivision (Yang et al., 1999; Mills et al., 1999). genesis. To study the role of -catenin in skin develop-Wnt/-catenin signaling, among other signaling sysment, we introduced a conditional mutation of the tems, was implicated in the development of skin, hair, gene in the epidermis and hair follicles using Cre/loxP and the related appendages in birds, the feathers (Nortechnology. When -catenin is mutated during emamly et al., 1999; Widelitz et al., 1999, 2000). Many combryogenesis, formation of placodes that generate hair ponents of the Wnt signaling system have been identifollicles is blocked. We show that -catenin is required fied: extracellular Wnt/wingless ligands activate Frizzled genetically downstream of tabby/downless and upreceptors and, through Dishevelled, induce an increase stream of bmp and shh in placode formation. If -catin cytoplasmic -catenin by preventing its degradation enin is deleted after hair follicles have formed, hair in proteasomes (for reviews, cf. Nusse, 1999; Huelsken is completely lost after the first hair cycle. Further and Behrens, 2000; Barker et al., 2000). Axin/Conductin, analysis demonstrates that -catenin is essential for in cooperation with the tumor suppressor gene product fate decisions of skin stem cells: in the absence of APC, promote -catenin degradation, which involves -catenin, stem cells fail to differentiate into follicular serine-threonine phosphorylation of the N terminus of keratinocytes, but instead adopt an epidermal fate. -catenin by GSK3 and subsequent ubiquitination (Rubinfeld et al., 1996; Behrens et al., 1998; Aberle et al., Introduction 1997; reviewed by Polakis, 2000). Upon Wnt signaling, -catenin accumulates in the cytoplasm and is trans-The hair follicle is generated during development in a ported to the nucleus, where it interacts with members of complex morphogenetic process that relies on a recipthe LEF/TCF family of transcription factors and activates rocal exchange of signals between epithelial and mesengene expression (Behrens et al., 1996; Molenaar et al., chymal cells in the forming of hair placodes (for reviews,
β-Catenin Activation Regulates Tissue Growth Non–Cell Autonomously in the Hair Stem Cell Niche
Science, 2014
Coordinated Hair Growth Wnt/β-catenin signaling is a key pathway that plays a conserved role in regulating stem cell function during adult tissue regeneration. Using time-lapse imaging of live mice, Deschene et al. (p. 1353 ) show that genetic activation of β-catenin within hair follicle stem cells generates axes of hair growth by coordinated cell divisions and cell movements, even when the normal niches—the dermal papillae—are laser-ablated. Activated β-catenin enhances Wnt ligand secretion, and these ligands can then activate Wnt signaling in adjacent cells that do not have activated β-catenin, indicating how activated stem cells could influence neighboring cells during normal growth and in cancer.
Journal of Dermatological Science, 2013
is only partly understood. Here we show that fibroblast growth factor (Fgf)18 is expressed in a hair stem cell niche throughout telogen, and that it regulates the hair cycle through the non-growth phases. When the Fgf18 gene is conditionally knocked out in keratin 5-positive epithelial cells in mice, telogen becomes very short, giving rise to a strikingly rapid succession of hair cycles. In wildtype mice, hair follicle growth during anagen is strongly suppressed by local delivery of FGF18 protein. Our results demonstrate that epithelial FGF18 signaling and its reduction in the milieu of hair stem cells are crucial for the maintenance of telogen and anagen phase, respectively.
Wnt/β-catenin signaling in dermal condensates is required for hair follicle formation
2014
Broad dermal Wnt signaling is required for patterned induction of hair follicle placodes and subsequent Wnt signaling in placode stem cells is essential for induction of dermal condensates, cell clusters of precursors for the hair follicle dermal papilla (DP). Progression of hair follicle formation then requires coordinated signal exchange between dermal condensates and placode stem cells. However, it remains unknown whether continued Wnt signaling in DP precursor cells plays a role in this process, largely due to the long-standing inability to specifically target dermal condensates for gene ablation. Here we use the Tbx18 Cre knockin mouse line to ablate the Wnt-responsive transcription factor β-catenin specifically in these cells at E14.5 during the first wave of guard hair follicle formation. In the absence of β-catenin, canonical Wnt signaling is effectively abolished in these cells. Sox2 þ dermal condensates initiate normally; however by E16.5 guard hair follicle numbers are strongly reduced and by E18.5 most whiskers and guard hair follicles are absent, suggesting that active Wnt signaling in dermal condensates is important for hair follicle formation to proceed after induction. To explore the molecular mechanisms by which Wnt signaling in dermal condensates regulates hair follicle formation, we analyze genome-wide the gene expression changes in embryonic β-catenin null DP precursor cells. We find altered expression of several signaling pathway genes, including Fgfs and Activin, both previously implicated in hair follicle formation. In summary, these data reveal a functional role of Wnt signaling in DP precursors for embryonic hair follicle formation and identify Fgf and Activin signaling as potential effectors of Wnt signaling-regulated events.
Suppression of Wnt/β-catenin signaling by EGF receptor is required for hair follicle development
Molecular biology of the cell, 2018
Mice that lack EGFR fail to develop a hair coat, but the mechanism responsible for this deficit is not completely understood. Here, we show that EGFR plays a critical role to attenuate Wnt/β-catenin signaling during postnatal hair follicle development. Genetic ablation of EGFR in mice resulted in increased mitotic activity in matrix cells, apoptosis in hair follicles and impaired differentiation of epithelial lineages that form hair. EGFR is activated in wild type hair follicle stem cells marked with SOX9 or NFATc1, and is essential to restrain proliferation, support stem cell numbers and their quiescence. We observed elevated levels of Wnt4, 6, 7b, 10a, 10b and 16 transcripts, and hyperactivation of the β-catenin pathway in EGFR knockout follicles. Using primary keratinocytes, we linked ligand-induced EGFR activation to suppression of nascent mRNA synthesis of Wnt genes. Overexpression of the Wnt antagonist sFRP1 in mice lacking EGFR demonstrated that elevated Wnts are a major caus...
β-catenin Activity in the Dermal Papilla Regulates Morphogenesis and Regeneration of Hair
Developmental Cell, 2010
The activity of keratinocytes in the hair follicle is regulated by signals from a specialized mesenchymal niche, the dermal papilla (DP). Here, mice expressing cre recombinase in the DP were developed to probe the interaction between follicular keratinocytes and the DP in vivo. Inactivation of the b-catenin gene within DP of fully developed hair follicles results in dramatically reduced proliferation of the progenitors and their progeny that generate the hair shaft, and, subsequently, premature induction of the destructive phase of the hair cycle. It also prevents regeneration of the cycling follicle from stem cells. Gene expression analysis reveals that b-catenin activity in the DP regulates signaling pathways, including FGF and IGF, that can mediate the DP's inductive effects. This study reveals a signaling loop that employs Wnt/ b-catenin signaling in both epithelial progenitor cells and their mesenchymal niche to govern and coordinate the interactions between these compartments to guide hair morphogenesis.