β-catenin Activity in the Dermal Papilla Regulates Morphogenesis and Regeneration of Hair

Enshell-Seijffers, David; Lindon, Catherine; Kashiwagi, Mariko; Morgan, Bruce

doi:10.1016/j.devcel.2010.01.016

Cited by 350 publications

(376 citation statements)

References 42 publications

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“…In contrast to the germline Bmal1 deletion, delayed anagen progression is not observed in mice with keratinocyte-specific deletion of Bmal1, indicating that in regulating this process BMAL1 acts either through the central clock, possibly through endocrine signaling, or through nonkeratinocyte cell types in the skin such as the dermal papilla (24) or preadipocytes (25), both of which have been shown to play a critical role in anagen initiation. Although a recent study showed that keratinocyte-specific deletion of Bmal1 altered the population size of bulge cells in the activation-ready state (12), this study also did not report delayed anagen initiation.…”

Section: Discussionmentioning

confidence: 86%

Brain and muscle Arnt-like protein-1 (BMAL1) controls circadian cell proliferation and susceptibility to UVB-induced DNA damage in the epidermis

Geyfman¹,

Kumar

Liu³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

225

322

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The role of the circadian clock in skin and the identity of genes participating in its chronobiology remain largely unknown, leading us to define the circadian transcriptome of mouse skin at two different stages of the hair cycle, telogen and anagen. The circadian transcriptomes of telogen and anagen skin are largely distinct, with the former dominated by genes involved in cell proliferation and metabolism. The expression of many metabolic genes is antiphasic to cell cycle-related genes, the former peaking during the day and the latter at night. Consistently, accumulation of reactive oxygen species, a byproduct of oxidative phosphorylation, and S-phase are antiphasic to each other in telogen skin. Furthermore, the circadian variation in S-phase is controlled by BMAL1 intrinsic to keratinocytes, because keratinocyte-specific deletion of Bmal1 obliterates time-of-day-dependent synchronicity of cell division in the epidermis leading to a constitutively elevated cell proliferation. In agreement with higher cellular susceptibility to UV-induced DNA damage during S-phase, we found that mice are most sensitive to UVB-induced DNA damage in the epidermis at night. Because in the human epidermis maximum numbers of keratinocytes go through S-phase in the late afternoon, we speculate that in humans the circadian clock imposes regulation of epidermal cell proliferation so that skin is at a particularly vulnerable stage during times of maximum UV exposure, thus contributing to the high incidence of human skin cancers.Arntl gene | circadian rhythm | UVB damage | cell cycle T he highly conserved circadian clock regulates organismal adaptation to the light:dark (LD) cycles caused by the rotation of the Earth (1). Located in the suprachiasmatic nucleus of the vertebrate hypothalamus, the central clock is an intrinsic pacemaker with a spontaneous firing rate and a nearly 24-h rhythmic gene expression. This central pacemaker is thought to synchronize peripheral clocks found in the vast majority of tissues and cells. The core circadian clock machinery is composed of the heterodimeric bHLH-PAS transcription factors CLOCK and BMAL1 that bind E-box elements to activate clock-controlled genes, as well as Period (Per1, 2, and 3) and Cryptochrome (Cry1 and 2). PERs and CRYs inhibit CLOCK/BMAL1 activity upon their translocation into the nucleus, thus constituting a negative arm in the circadian feedback loop. CLOCK/ BMAL1 also activate expression of nuclear receptors ROR and REV-ERBα, which in turn respectively activate and inhibit the transcription of Bmal1 and other target genes containing retinoic acid-related orphan receptor response elements.Although the circadian clock is active in most mammalian tissues, the battery of genes under circadian regulation is largely tissue specific (2), suggesting that the circadian clock modulates physiological processes unique to each organ. Here we have focused on the role of the clock within skin, an organ dominated on the one hand by the cycling hair follicles and on the other by the continuously r...

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Section: Discussionmentioning

confidence: 86%

Brain and muscle Arnt-like protein-1 (BMAL1) controls circadian cell proliferation and susceptibility to UVB-induced DNA damage in the epidermis

Geyfman¹,

Kumar

Liu³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

225

322

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“…FACS-isolated DP cells rapidly lose their inductive properties upon in vitro culture, which can be rescued by addition of Wnt3a (Kishimoto et al 2000). b-Catenin deletion specifically in DP cells results in a strong decrease in HF progenitor proliferation and HF terminal differentiation, leading to a premature entry in catagen and preventing bulge SCs from reinitiating a novel cycle of HF regeneration (Enshell-Seijffers et al 2010). In adult epidermis, b-catenin regulates the expression of nephronectin by HF SCs, which in turn regulates the attachment of the arrector pili muscle to the top of the bulge (Fujiwara et al 2011).…”

Section: Hf Morphogenesis and Cyclingmentioning

confidence: 99%

Development and Homeostasis of the Skin Epidermis

Sotiropoulou

Blanpain

2012

Cold Spring Harbor Perspectives in Biology

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SUMMARYThe skin epidermis is a stratified epithelium that forms a barrier that protects animals from dehydration, mechanical stress, and infections. The epidermis encompasses different appendages, such as the hair follicle (HF), the sebaceous gland (SG), the sweat gland, and the touch dome, that are essential for thermoregulation, sensing the environment, and influencing social behavior. The epidermis undergoes a constant turnover and distinct stem cells (SCs) are responsible for the homeostasis of the different epidermal compartments. Deregulation of the signaling pathways controlling the balance between renewal and differentiation often leads to cancer formation.

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“…Robust TGF-b and Bmp signals act as 'activation breaks', rendering bulge cells dormant during the resting phase of the hair cycle (telogen) [9][10][11] . At the onset of the growth phase (anagen), bulge cells respond to Wnt signals by migrating into the lower proliferative hair germ region, where they contribute to follicle growth [12][13][14][15] . Subsequently, at mid-anagen, the bulge undergoes a second round of activation, which replenishes cells lost at the onset of anagen 2,3 .…”

mentioning

confidence: 99%

The circadian molecular clock creates epidermal stem cell heterogeneity

Janich

Pascual

Merlos‐Suárez

et al. 2011

Nature

282

290

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Murine epidermal stem cells undergo alternate cycles of dormancy and activation, fuelling tissue renewal. However, only a subset of stem cells becomes active during each round of morphogenesis, indicating that stem cells coexist in heterogeneous responsive states. Using a circadian-clock reporter-mouse model, here we show that the dormant hair-follicle stem cell niche contains coexisting populations of cells at opposite phases of the clock, which are differentially predisposed to respond to homeostatic cues. The core clock protein Bmal1 modulates the expression of stem cell regulatory genes in an oscillatory manner, to create populations that are either predisposed, or less prone, to activation. Disrupting this clock equilibrium, through deletion of Bmal1 (also known as Arntl) or Per1/2, resulted in a progressive accumulation or depletion of dormant stem cells, respectively. Stem cell arrhythmia also led to premature epidermal ageing, and a reduction in the development of squamous tumours. Our results indicate that the circadian clock fine-tunes the temporal behaviour of epidermal stem cells, and that its perturbation affects homeostasis and the predisposition to tumorigenesis.Epidermal stem cells ensure that skin homeostasis is maintained. Murine epidermal stem cells are located either at the permanent portion of the hair follicle-termed the bulge-and are exclusively responsible for hair cycling [1][2][3][4] ; or at the junction between the epidermis and the hair follicle (isthmus), and feed into the epidermis and sebaceous glands [5][6][7] . In addition, a continuous proliferation of basal interfollicular epidermal cells ensures daily epidermal maintenance 8 .Bulge stem cells undergo bouts of activation followed by periods of dormancy, to establish hair follicle cycling. Robust TGF-b and Bmp signals act as 'activation breaks', rendering bulge cells dormant during the resting phase of the hair cycle (telogen) [9][10][11] . At the onset of the growth phase (anagen), bulge cells respond to Wnt signals by migrating into the lower proliferative hair germ region, where they contribute to follicle growth [12][13][14][15] . Subsequently, at mid-anagen, the bulge undergoes a second round of activation, which replenishes cells lost at the onset of anagen 2,3 . However, the response of bulge stem cells to activating stimuli is a heterogeneous process, as only a subset of them become active during either stage of activation 12,13 . The nature of such niche heterogeneity is currently unknown. Importantly, perturbing the equilibrium between the responsive and non-responsive stem cell states causes tissue malfunction and increases the risk of carcinogenesis [16][17][18][19][20] .Here, we analysed the role of the molecular clock in fine-tuning the function of epidermal stem cells. The mammalian clock machinery anticipates and synchronizes vital functions related to the physiological circadian needs of the organism 21 . The core molecular clock is established by a positive limb, composed of heterodimers of the transcription fa...

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β-catenin Activity in the Dermal Papilla Regulates Morphogenesis and Regeneration of Hair

Cited by 350 publications

References 42 publications

Brain and muscle Arnt-like protein-1 (BMAL1) controls circadian cell proliferation and susceptibility to UVB-induced DNA damage in the epidermis

Brain and muscle Arnt-like protein-1 (BMAL1) controls circadian cell proliferation and susceptibility to UVB-induced DNA damage in the epidermis

Development and Homeostasis of the Skin Epidermis

The circadian molecular clock creates epidermal stem cell heterogeneity

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