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Dlx3 is a crucial regulator of hair follicle differentiation and cycling.

ABSTRACT: Dlx homeobox transcription factors regulate epidermal, neural and osteogenic cellular differentiation. Here, we demonstrate the central role of Dlx3 as a crucial transcriptional regulator of hair formation and regeneration. The selective ablation of Dlx3 in the epidermis results in complete alopecia owing to failure of the hair shaft and inner root sheath to form, which is caused by the abnormal differentiation of the cortex. Significantly, we elucidate the regulatory cascade that positions Dlx3 downstream of Wnt signaling and as an upstream regulator of other transcription factors that regulate hair follicle differentiation, such as Hoxc13 and Gata3. Colocalization of phospho-Smad1/5/8 and Dlx3 is consistent with a regulatory role for BMP signaling to Dlx3 during hair morphogenesis. Importantly, mutant catagen follicles undergo delayed regression and display persistent proliferation. Moreover, ablation of Dlx3 expression in the telogen bulge stem cells is associated with a loss of BMP signaling, precluding re-initiation of the hair follicle growth cycle. Taken together with hair follicle abnormalities in humans with Tricho-Dento-Osseous (TDO) syndrome, an autosomal dominant ectodermal dysplasia linked to mutations in the DLX3 gene, our results establish that Dlx3 is essential for hair morphogenesis, differentiation and cycling programs.

SUBMITTER: Hwang J

PROVIDER: S-EPMC2707782 | biostudies-literature | 2008 Sep

REPOSITORIES: biostudies-literature

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Dlx3 is a crucial regulator of hair follicle differentiation and cycling.

Hwang Joonsung J Mehrani Taraneh T Millar Sarah E SE Morasso Maria I MI

Development (Cambridge, England) 20080806 18

Dlx homeobox transcription factors regulate epidermal, neural and osteogenic cellular differentiation. Here, we demonstrate the central role of Dlx3 as a crucial transcriptional regulator of hair formation and regeneration. The selective ablation of Dlx3 in the epidermis results in complete alopecia owing to failure of the hair shaft and inner root sheath to form, which is caused by the abnormal differentiation of the cortex. Significantly, we elucidate the regulatory cascade that positions Dlx3 ...[more]

PMID: 18684741

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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.

Dataset Information

Dlx3 is a crucial regulator of hair follicle differentiation and cycling.

Publications

Dlx3 is a crucial regulator of hair follicle differentiation and cycling.

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