Patterns of Hairless (hr) Gene Expression in Mouse Hair Follicle Morphogenesis and Cycling

Panteleyev, Andrey A.; Paus, Ralf; Christiano, Angela M.

doi:10.1016/s0002-9440(10)64621-4

Cited by 71 publications

(56 citation statements)

References 31 publications

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“…Similarly, hr expression has been reported in hair follicles (including inner root sheath and matrix cells) and in the interfollicular epidermis (27,60). To determine whether the interaction between Hr and VDR that we have defined biochemically potentially occurs in vivo, we assessed whether hr and VDR are coexpressed in skin.…”

Section: Resultsmentioning

confidence: 91%

Physical and Functional Interaction between the Vitamin D Receptor and Hairless Corepressor, Two Proteins Required for Hair Cycling

Hsieh

Sisk

Jurutka

et al. 2003

Journal of Biological Chemistry

206

201

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Both the vitamin D receptor (VDR) and hairless (hr) genes play a role in the mammalian hair cycle, as inactivating mutations in either result in total alopecia. VDR is a nuclear receptor that functions as a ligand-activated transcription factor, whereas the hairless gene product (Hr) acts as a corepressor of both the thyroid hormone receptor (TR) and the orphan nuclear receptor, ROR␣. In the present study, we show that VDR-mediated transactivation is strikingly inhibited by coexpression of rat Hr. The repressive effect of Hr is observed on both synthetic and naturally occurring VDR-responsive promoters and also when VDR-mediated transactivation is augmented by overexpression of its heterodimeric partner, retinoid X receptor. Utilizing in vitro pull down methods, we find that Hr binds directly to VDR but insignificantly to nuclear receptors that are not functionally repressed by Hr. Coimmunoprecipitation data demonstrate that Hr and VDR associate in a cellular milieu, suggesting in vivo interaction. The Hr contact site in human VDR is localized to the central portion of the ligand binding domain, a known corepressor docking region in other nuclear receptors separate from the activation function-2 domain. Coimmunoprecipitation and functional studies of Hr deletants reveal that VDR contacts a C-terminal region of Hr that includes motifs required for TR and ROR␣ binding. Finally, in situ hybridization analysis of hr and VDR mRNAs in mouse skin demonstrates colocalization in cells of the hair follicle, consistent with a hypothesized intracellular interaction between these proteins to repress VDR target gene expression, in vivo.Nuclear receptors comprise a family of ligand-activated transcription factors that coordinate physiological and developmental processes by regulating specific changes in gene expression (1, 2). The vitamin D receptor (VDR) 1 mediates signaling by 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) and is a member of the thyroid hormone/retinoic acid receptor subfamily of nuclear receptors that heterodimerize with the retinoid X receptor (RXR) on direct repeat hormone-responsive elements in the promoters of regulated genes (3, 4). Binding of liganded VDR⅐RXR to a vitamin D-responsive element (VDRE) in target genes such as osteocalcin, osteopontin, and vitamin D 24-hydroxylase (CYP24) is accompanied by the recruitment of coactivator proteins (5). VDR coactivators such as steroid receptor coactivator-1 (6), NCoA-62 (7), and vitamin D receptor interacting protein 205 (8) stimulate transcriptional activation by facilitating chromatin remodeling and/or attraction of RNA polymerase II. Although some unliganded nuclear receptors (thyroid hormone and retinoic acid receptors) can mediate repression through association with corepressors such as nuclear receptor corepressor (N-CoR) (9) and silencing mediator for retinoic acid and thyroid hormone receptors (SMRT) (10), evidence suggests that VDR does not associate strongly with these corepressors (9 -12).Targeted gene deletion studies in mice (13, 14) and inactivat...

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Section: Resultsmentioning

confidence: 91%

Physical and Functional Interaction between the Vitamin D Receptor and Hairless Corepressor, Two Proteins Required for Hair Cycling

Hsieh

Sisk

Jurutka

et al. 2003

Journal of Biological Chemistry

206

201

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“…We carried out reverse transcriptase-PCR analysis for Tcl1 on wt RNA extracted from the dorsal skins of 6-weeks-old mice, 1, 3, 6 and 8 days after depilation, corresponding to synchronised early anagen stages I, II, III and IV of the HF development and skin differentiation (Panteleyev et al, 2000). The anagen phase involves the complete re-growth and regeneration of the cycling portion of HF.…”

Section: Resultsmentioning

confidence: 99%

The Tcl1 oncogene defines secondary hair germ cells differentiation at catagen–telogen transition and affects stem-cell marker CD34 expression

et al. 2009

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Overexpression of the TCL1 gene family plays a role in the onset of T-cell leukemias in mice and in humans. The Tcl1 gene is tightly regulated during early embryogenesis in which it participates in embryonic stem (ES)-cells proliferation and during lymphoid differentiation. Here, we provide evidences that Tcl1 is also important in mouse hair follicle (HF) and skin homeostasis. We found that Tcl1 À/À adult mice exhibit hair loss, leading to alopecia with extensive skin lesions. By analysing Tcl1 expression in the wild-type (wt) skin through different stages of hair differentiation, we observe high levels in the secondary hair germ (HG) cells and hair bulges, during early anagen and catagen-telogen transition phases. The loss of Tcl1 does not result in apparent skin morphological defects during embryonic development and at birth, but its absence causes a reduction of proliferation in anagen HFs. Importantly, we show the that absence of Tcl1 induces a significant loss of the stem-cell marker CD34 (but not a6-integrin) expression in the bulge cells, which is necessary to maintain stem-cell characteristics. Therefore, our findings indicate that Tcl1 gene(s) might have important roles in hair formation, by its involvement in cycling and self-renewal of transient amplifying (TA) and stem-cell (SC) populations.

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“…Despite otherwise complete HF destruction after the first entry into catagen, mutant mice with functionally defective hairless protein seem to retain a residual HFeSC pool (Panteleyev et al, 1999;Panteleyev et al, 2000a;Panteleyev et al, 2000b). Likewise, even in the absence of functional VDR HFs develop, and a HFeSC niche establishes itself.…”

Section: Insights On Hfesc Endocrinology From Mouse Geneticsmentioning

confidence: 99%

“…In mice and man, VDR-mediated signaling is essential for normal HF development, growth, and cycling, and VDR mutations result in alopecia. The product of the hairless gene -a zinc finger protein like VDR, whose mutation, by itself, produces a very similar hair phenotype in mice and man as VDR mutants -serves as a nuclear co-repressor for VDR (Bergman et al, 2005; Bikle et al, 2006;Miller et al, 2001;.Despite otherwise complete HF destruction after the first entry into catagen, mutant mice with functionally defective hairless protein seem to retain a residual HFeSC pool (Panteleyev et al, 1999;Panteleyev et al, 2000a;Panteleyev et al, 2000b). Likewise, even in the absence of functional VDR HFs develop, and a HFeSC niche establishes itself.…”

mentioning

confidence: 99%

(Neuro-)endocrinology of epithelial hair follicle stem cells

Paus

Arck

Tiede

2008

Molecular and Cellular Endocrinology

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The hair follicle is a repository of different types of somatic stem cells. However, even though the hair follicle is both a prominent target organ and a potent, non-classical site of production and/or metabolism of numerous polypetide-and steroid hormones, neuropeptides, neurotransmitters and neurotrophins, the (neuro-) endocrine controls of hair follicle epithelial stem cell (HFeSC) biology remain to be systematically explored.Focussing on HFeSCs, we attempt here to offer a "roadmap through terra incognita" by listing key open questions, by exploring endocrinologically relevant HFeSC gene profiling and mouse genomics data, and by sketching several clinically relevant pathways via which systemic and/or locally generated (neuro-)endocrine signals might impact on HFeSC. Exemplarily, we discuss e.g. the potential roles of glucocorticoid and vitamin D receptors, the hairless gene product, thymic hormones, bone morphogenic proteins (BMPs) and their antagonists, and Skg-3 in HFeSC biology. Furthermore, we elaborate on the potential role of nerve growth factor (NGF) and substance P-dependent neurogenic inflammation in HFeSC damage, and explore how neuroendocrine signals may influence the balance between maintenance and destruction of hair follicle immune privilege, which protects these stem cells and their progeny. These considerations call for a concerted research effort to dissect the (neuro)-endocrinology of HFeSCs much more systematically than before. The hair follicle (HF) and its special, associated mesenchyme (i.e. the connective tissue sheath, CTS) are repositories of different types of somatic stem cells (epithelial, mesenchymal, neural, mesenchymal) (Cotsarelis, 2006; Kruse et al., 2006;Millar, 2005;Ohyama et al., 2006;Tiede et al. 2007;Waters et al., 2007;Yu et al., 2006). These HFassociated stem cell populations are critical for HF development and function, including HF pigmentation (Nishimura et al., 2002(Nishimura et al., , 2005Sarin and Artandi, 2007). Fig. 1 shows several important, recognized hair follicle-associated stem cell populations and their bestcharacterized location(s) in the pilosebaceous unit, though it must be kept in mind that the indicated ones are unlikely to be the only stem cell population associated with mammalian skin appendages (Tiede et al. 2007). Clinical importance of hair follicle stem cellsHair follicle epithelial stem cells (HFeSCs) are clinically important, since they can be key targets for pathological processes, such as an autoaggressive inflammatory cell attack on HFeSC, e.g. in lupus erythematosus or lichen planopilaris, where the destruction of bulge HFeSCs (see Fig.1) abolishes the hair follicle's capacity to cycle and to rhythmically regenerate itself, leading to scarring alopecia (Cotsarelis, 2006;Hiroi et al., 2006;Mobini et al., 2005;Paus, 2006). Likewise, a gradual loss of HF melanocyte stem cells may exhaust the HF pigmentary unit's capacity to generate itself and to produce melanin and thus likely plays a key role in hair graying (Commo et al., 2004;...

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Patterns of Hairless (hr) Gene Expression in Mouse Hair Follicle Morphogenesis and Cycling

Cited by 71 publications

References 31 publications

Physical and Functional Interaction between the Vitamin D Receptor and Hairless Corepressor, Two Proteins Required for Hair Cycling

Physical and Functional Interaction between the Vitamin D Receptor and Hairless Corepressor, Two Proteins Required for Hair Cycling

The Tcl1 oncogene defines secondary hair germ cells differentiation at catagen–telogen transition and affects stem-cell marker CD34 expression

(Neuro-)endocrinology of epithelial hair follicle stem cells

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