Runx1 modulates adult hair follicle stem cell emergence and maintenance from distinct embryonic skin compartments

Osorio, Karen M.; Lilja, Karin; Tumbar, Tudorita

doi:10.1083/jcb.201006068

Cited by 65 publications

(66 citation statements)

References 49 publications

(129 reference statements)

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“…This may be responsible for the high error bars that did not allow us to detect significant tumor differences between WT and p21 KO mice, as previously reported (19,20). Upon DMBA/TPA treatment initiated at the second telogen, Runx1 KO mice, however, had significantly (P < 0.05, weeks [11][12][13][14][15][16][17][18][19][20] fewer papillomas compared with WT, as expected. At 15-16 wk of TPA treatment, the dKO mice had significantly more tumors than the Runx1 KO (P < 0.05) but fewer than WT and p21 KO mice (Fig.…”

Section: P21 Reduces Proliferation Of Hfscs In Vitro and Controls Thesupporting

confidence: 57%

“…In particular Runx1, a transcription factor of the Runt family member of cancer genes (14), promotes HFSC activation from quiescence to migrate, proliferate, and differentiate at telogen (15) and self-renew at anagen (16) and controls timely emergence of HFSCs and proper maturation during embryogenesis (17). Moreover, Runx1 is indispensable for skin tumorigenesis and for keratinocyte growth in culture.…”

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confidence: 99%

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Runx1 and p21 synergistically limit the extent of hair follicle stem cell quiescence in vivo

Lee

Hoi

Lilja

et al. 2013

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

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Mechanisms of tissue stem cell (SC) quiescence control are important for normal homeostasis and for preventing cancer. Cyclin-dependent kinase inhibitors (CDKis) are known inhibitors of cell cycle progression. We document CDKis expression in vivo during hair follicle stem cell (HFSC) homeostasis and find p21 (cyclin-dependent kinase inhibitor 1a, Cdkn1a), p57, and p15 up-regulated at quiescence onset. p21 appears important for HFSC timely onset of quiescence. Conversely, we find that Runx1 (runt related transcription factor 1), which is known for promoting HFSC proliferation, represses p21, p27, p57, and p15 transcription in HFSC in vivo. Intriguingly, in cell culture, tumors, and normal homeostasis, Runx1 and p21 interplay modulates proliferation in opposing directions under the different conditions. Unexpectedly, Runx1 and p21 synergistically limit the extent of HFSC quiescence in vivo, which antagonizes the role of p21 as a cell cycle inhibitor. Importantly, we find in cultured keratinocytes that Runx1 and p21 bind to the p15 promoter and synergistically repress p15 mRNA transcription, thereby restraining cell cycle arrest. This documents a surprising ability of a CDKi (p21) to act as a direct transcriptional repressor of another CDKi (p15). We unveil a robust in vivo mechanism that enforces quiescence of HFSCs, and a context-dependent role of a CDKi (p21) to limit quiescence of SCs, potentially by directly down-regulating mRNA levels of (an)other CDKi(s).AML1 | skin | malignancy | pulse-chase | H2B-GFP

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Section: P21 Reduces Proliferation Of Hfscs In Vitro and Controls Thesupporting

confidence: 57%

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confidence: 99%

Runx1 and p21 synergistically limit the extent of hair follicle stem cell quiescence in vivo

Lee

Hoi

Lilja

et al. 2013

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

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“…During embryonic development, Runx1 is expressed in both the embryonic HF and its underlying mesenchyme (Osorio et al 2008(Osorio et al , 2011. In adult mice, Runx1 is expressed in the bulge, HG, and HF progenitors.…”

Section: Hf Morphogenesis and Cyclingmentioning

confidence: 99%

“…Deletion of Runx1 in the skin epidermis during embryonic development results in bulge SCs that fail to actively proliferate during telogen-to-anagen transition, leading to delayed HF regeneration (Osorio et al 2008). In contrast, Runx1 expression in the embryonic mesenchyme is essential for HF differentiation and long-term maintenance of bulge SCs (Osorio 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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“…The lack of immortal strands left us bare handed in identifying unique cellular characteristics in these tissue stem cells. Some genes are preferentially expressed in hair follicle stem cells, and of these some specific transcription factors such as Tbx1 and Runx1, to name a few, drive the hair follicle stem cell self-renewal and proliferation (Osorio et al, 2008, Hoi et al, 2010, Osorio et al, 2011, Chen et al, 2012, Lee et al, 2013) and Dlx3 drives their differentiation (Hwang et al, 2008). Undoubtedly more transcription factors will surface that will likely interface with chromatin modifying enzymes, microRNAs, and long non-coding RNAs to control the tissue stem cell behaviour.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Adult hair follicle stem cells do not retain the older DNA strands in vivo during normal tissue homeostasis

Waghmare

Tumbar

2013

Chromosome Res

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Tissue stem cells have been proposed to segregate the chromosomes asymmetrically (in a non-random manner) thereby retaining preferentially the older ‘immortal’ DNA strand bearing the stemness characteristics into one daughter cell, whereas the newly synthesized strands are segregated to the other daughter cells that will commit to differentiation. Moreover, this non-random segregation would protect the stem cell genome from accumulating multiple mutations during repeated DNA replication. This long-standing hypothesis remains an active subject of study due to conflicting results for some systems, and lack of consistency among different tissue stem cell populations. In this review we will focus on work done in the hair follicle, which is one of the best understood vertebrate tissue stem cell systems to date. In cell culture analysis of paired cultured keratinocytes derived from hair follicle stem cells revealed non-random segregation of chromosome with respect to the older DNA strand. In vivo, the hair follicle stem cells appear to self-renew and differentiate at different phases of their homeostatic cycle. The fate decisions occur in quiescence when some stem cells migrate out of their niche and commit to differentiation without self-renewal. The stem cells left behind in the niche self-renew symmetrically and randomly segregate the chromosomes at each division, making more stem cells. This model seems to apply to at least a few other vertebrate tissue stem cells in vivo.

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Runx1 modulates adult hair follicle stem cell emergence and maintenance from distinct embryonic skin compartments

Abstract: Runx1 controls timing of adult HSFC and short-term progenitor emergence in the embryonic epithelium and HFSC differentiation and long-term skin integrity in embryonic mesenchyme.

Cited by 65 publications

References 49 publications

Runx1 and p21 synergistically limit the extent of hair follicle stem cell quiescence in vivo

Runx1 and p21 synergistically limit the extent of hair follicle stem cell quiescence in vivo

Development and Homeostasis of the Skin Epidermis

Adult hair follicle stem cells do not retain the older DNA strands in vivo during normal tissue homeostasis

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