Immunolocalization of Wnt5a during the hair cycle and its role in hair shaft growth in mice.
ABSTRACT Previous studies have shown that the Wnt signaling pathway plays an important role in the growth and development of hair follicles. It has been generally accepted that Wnt5a, a non-canonical Wnt gene, inhibits the Wnt/β-catenin signaling pathway. Several reports have addressed its mRNA expression in embryonic and postnatal hair follicles, but its exact role in the growth of hair follicles is currently unknown. In this study, we investigated the immunolocalization of Wnt5a protein in pelages of the dorsal skin and whisker follicles of mice. We found that in the anagen phase, dermal papilla cells showed the highest staining levels of Wnt5a protein, while in the catagen and the telogen phases the staining levels were lower. During the growth stage, Wnt5a protein was prominently located in the matrix and precortex cells in addition to the inner root sheath, outer root sheath and the dermal papilla. As the hair cycle progresses, the immunostaining of Wnt5a was gradually decreased in the catagen phase and was located in the bulge and secondary hair germ in the telogen phase. This Wnt5a immunostaining profile was consistent between dorsal skin pelages and whisker follicles. Furthermore, in an in vitro study using whisker follicle organ culture, we demonstrated that the growth of the hair shaft was significantly inhibited by adenovirus Wnt5a. Our findings suggest that Wnt5a is a dynamic factor in the hair cycle and it is important for the regulation of hair shaft growth.
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ABSTRACT: Findings of recent studies have demonstrated modulation of Wnt/β-catenin signalling by Wnt5a, which is highly expressed in hair follicular dermal papilla (DP) in vivo. Here, we investigated the question of whether Wnt5a can affect canonical Wnt/β-catenin signalling in DP cells. Treatment with Wnt5a resulted in attenuation of Wnt3a-mediated elevation of β-catenin signalling, which was increased by Wnt5a siRNA transfection in cultured DP cells, as examined by reporter assay. In addition, treatment with Wnt5a resulted in repressed Wnt3a-mediated expression of Axin2, EP2 and LEF1 in cultured DP cells, whereas Wnt5a siRNA transfection resulted in increased Wnt3a-mediated expression of the genes in isolated DPs of cultured hair follicles. Moreover, treatment with Wnt5a resulted in attenuation of Wnt3a-mediated accumulation of β-catenin in the nucleus in DP cells. Our data strongly suggest that Wnt5a acts as an autocrine factor and attenuates canonical Wnt signalling pathway in human DP cells.Experimental Dermatology 03/2013; 22(3):229-231. · 3.58 Impact Factor
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ABSTRACT: Hair cycling is a prime example of stem cell dependent tissue regeneration and replenishment, and its regulatory mechanisms remain poorly understood. In the present study, we evaluated the effect of a blockage in terminal keratinocytic lineage differentiation in the Foxn1(-/-) nude phenotype on the epithelial progeny. Most notably we found a constitutive upregulation of LIM homeobox protein 2 (Lhx2), a marker gene of epithelial stem cellness indispensible for hair cycle progression. However, histological evidence along with an erratic, acyclic rise of otherwise suppressed CyclinD1 levels along with several key markers of keratinocyte lineage differentiation indicate a frustrated expansion of epithelial stem cell niches in skin. In addition, CD49f/CD34/CD200-based profiling demonstrated highly significant shifts in subpopulations of epithelial progeny. Intriguingly this appeared to include the expansion of Oct4+ stem cells in dermal fractions of skin isolates in the Foxn1 knock-out opposed to wild type. Overall our findings indicate that the Foxn1(-/-) phenotype has a strong impact on epithelial progeny and thus offers a promising model to study maintenance and regulation of stem cell niches within skin not feasible in other in vitro or in vivo models.PLoS ONE 01/2013; 8(5):e64223. · 3.73 Impact Factor
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ABSTRACT: Although hair forms (straight, curly, wavy, etc.) are present in apparently infinite variations, each fibre can be reduced to a finite sequence of tandem segments of just three types: straight, bent/curly, or twisted. Hair forms can thus be regarded as resulting from genetic pathways that induce, reverse or modulate these basic curvature modes. However, physical interconversions between twists and curls demonstrate that strict one-to-one correspondences between them and their genetic causes do not exist. Current hair-curvature theories do not distinguish between bending and twisting mechanisms. We here introduce a multiple papillary centres (MPC) model which is particularly suitable to explain twisting. The model combines previously known features of hair cross-sectional morphology with partially/completely separated dermal papillae within single follicles, and requires such papillae to induce differential growth rates of hair cortical material in their immediate neighbourhoods. The MPC model can further help to explain other, poorly understood, aspects of hair growth and morphology. Separate bending and twisting mechanisms would be preferentially affected at the major or minor ellipsoidal sides of fibres, respectively, and together they exhaust the possibilities for influencing hair-form phenotypes. As such they suggest dialectic for hair-curvature development. We define a natural-dialectic (ND) which could take advantage of speculative aspects of dialectic, but would verify its input data and results by experimental methods. We use this as a top-down approach to first define routes by which hair bending or twisting may be brought about and then review evidence in support of such routes. In particular we consider the wingless (Wnt) and mammalian target of rapamycin (mTOR) pathways as paradigm pathways for molecular hair bending and twisting mechanisms, respectively. In addition to the Wnt canonical pathway, the Wnt/Ca(2+) and planar cell polarity (PCP) pathways, and others, can explain many alternatives and specific variations of hair bending phenotypes. Mechanisms for hair papilla budding or its division by bisection or fission can explain MPC formation. Epithelial-to-mesenchymal (EMT) and mesenchymal-to-epithelial (MET) transitions, acting in collaboration with epithelial-mesenchymal communications are also considered as mechanisms affecting hair growth and its bending and twisting. These may be treated as sub-mechanisms of an overall development from neural-crest stem cell (NCSC) lineages to differentiated hair follicle (HF) cell types, thus providing a unified framework for hair growth and development.Biological Reviews 03/2014; · 10.26 Impact Factor