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      Lrig1 Expression Defines a Distinct Multipotent Stem Cell Population in Mammalian Epidermis

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          Summary

          Lrig1 is a marker of human interfollicular epidermal stem cells and helps maintain stem cell quiescence. We show that, in mouse epidermis, Lrig1 defines the hair follicle junctional zone adjacent to the sebaceous glands and infundibulum. Lrig1 is a Myc target gene; loss of Lrig1 increases the proliferative capacity of stem cells in culture and results in epidermal hyperproliferation in vivo. Lrig1-expressing cells can give rise to all of the adult epidermal lineages in skin reconstitution assays. However, during homeostasis and on retinoic acid stimulation, they are bipotent, contributing to the sebaceous gland and interfollicular epidermis. β-catenin activation increases the size of the junctional zone compartment, and loss of Lrig1 causes a selective increase in β-catenin-induced ectopic hair follicle formation in the interfollicular epidermis. Our results suggest that Lrig1-positive cells constitute a previously unidentified reservoir of adult mouse interfollicular epidermal stem cells.

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          Most cited references38

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          Identification of c-MYC as a target of the APC pathway.

          The adenomatous polyposis coli gene (APC) is a tumor suppressor gene that is inactivated in most colorectal cancers. Mutations of APC cause aberrant accumulation of beta-catenin, which then binds T cell factor-4 (Tcf-4), causing increased transcriptional activation of unknown genes. Here, the c-MYC oncogene is identified as a target gene in this signaling pathway. Expression of c-MYC was shown to be repressed by wild-type APC and activated by beta-catenin, and these effects were mediated through Tcf-4 binding sites in the c-MYC promoter. These results provide a molecular framework for understanding the previously enigmatic overexpression of c-MYC in colorectal cancers.
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            Stem cells and niches: mechanisms that promote stem cell maintenance throughout life.

            Niches are local tissue microenvironments that maintain and regulate stem cells. Long-predicted from mammalian studies, these structures have recently been characterized within several invertebrate tissues using methods that reliably identify individual stem cells and their functional requirements. Although similar single-cell resolution has usually not been achieved in mammalian tissues, principles likely to govern the behavior of niches in diverse organisms are emerging. Considerable progress has been made in elucidating how the microenvironment promotes stem cell maintenance. Mechanisms of stem cell maintenance are key to the regulation of homeostasis and likely contribute to aging and tumorigenesis when altered during adulthood.
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              Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis.

              Inconsistent with the view that hair follicle stem cells reside in the matrix area of the hair bulb, we found that label-retaining cells exist exclusively in the bulge area of the mouse hair follicle. The bulge consists of a subpopulation of outer root sheath cells located in the midportion of the follicle at the arrector pili muscle attachment site. Keratinocytes in the bulge area are relatively undifferentiated ultrastructurally. They are normally slow cycling, but can be stimulated to proliferate transiently by TPA. Located in a well-protected and nourished environment, these cells mark the lower end of the "permanent" portion of the follicle. Our findings, plus a reevaluation of the literature, suggest that follicular stem cells reside in the bulge region, instead of the lower bulb. This new view provides insights into hair cycle control and the possible involvement of hair follicle stem cells in skin carcinogenesis.
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                Author and article information

                Contributors
                Journal
                Cell Stem Cell
                Cell Stem Cell
                Cell Press
                1934-5909
                1875-9777
                08 May 2009
                08 May 2009
                : 4
                : 5
                : 427-439
                Affiliations
                [1 ]Laboratory for Epidermal Stem Cell Biology, Wellcome Trust Centre for Stem Cell Research, University of Cambridge, Cambridge CB2 1QR, UK
                [2 ]Laboratory for Epithelial Stem Cell Homeostasis and Cancer, Wellcome Trust Centre for Stem Cell Research, University of Cambridge, Cambridge CB2 1QR, UK
                [3 ]Department of Regenerative Dermatology, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita-shi, Osaka 565-0871, Japan
                [4 ]Epithelial Cell Biology Laboratory, Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge CB2 0RE, UK
                Author notes
                []Corresponding author fiona.watt@ 123456cancer.org.uk
                Article
                STEM435
                10.1016/j.stem.2009.04.014
                2698066
                19427292
                ea26f87e-61a1-4bc2-9b22-9dcb2a2f53bc
                © 2009 ELL & Excerpta Medica.

                This document may be redistributed and reused, subject to certain conditions.

                History
                : 24 October 2008
                : 25 March 2009
                : 20 April 2009
                Categories
                Article

                Molecular medicine
                stemcell
                Molecular medicine
                stemcell

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