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      Atopic Dermatitis-Like Disease and Associated Lethal Myeloproliferative Disorder Arise from Loss of Notch Signaling in the Murine Skin

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          Abstract

          Background

          The Notch pathway is essential for proper epidermal differentiation during embryonic skin development. Moreover, skin specific loss of Notch signaling in the embryo results in skin barrier defects accompanied by a B-lymphoproliferative disease. However, much less is known about the consequences of loss of Notch signaling after birth.

          Methodology and Principal Findings

          To study the function of Notch signaling in the skin of adult mice, we made use of a series of conditional gene targeted mice that allow inactivation of several components of the Notch signaling pathway specifically in the skin. We demonstrate that skin-specific inactivation of Notch1 and Notch2 simultaneously, or RBP-J, induces the development of a severe form of atopic dermatitis (AD), characterized by acanthosis, spongiosis and hyperkeratosis, as well as a massive dermal infiltration of eosinophils and mast cells. Likewise, patients suffering from AD, but not psoriasis or lichen planus, have a marked reduction of Notch receptor expression in the skin. Loss of Notch in keratinocytes induces the production of thymic stromal lymphopoietin (TSLP), a cytokine deeply implicated in the pathogenesis of AD. The AD-like associated inflammation is accompanied by a myeloproliferative disorder (MPD) characterized by an increase in immature myeloid populations in the bone marrow and spleen. Transplantation studies revealed that the MPD is cell non-autonomous and caused by dramatic microenvironmental alterations. Genetic studies demontrated that G-CSF mediates the MPD as well as changes in the bone marrow microenvironment leading to osteopenia.

          Significance

          Our data demonstrate a critical role for Notch in repressing TSLP production in keratinocytes, thereby maintaining integrity of the skin and the hematopoietic system.

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          Most cited references56

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          Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice

          Interleukin 7 (IL-7) stimulates the proliferation of B cell progenitors, thymocytes, and mature T cells through an interaction with a high affinity receptor (IL-7R) belonging to the hematopoietin receptor superfamily. We have further addressed the role of IL-7 and its receptor during B and T cell development by generating mice genetically deficient in IL-7R. Mutant mice display a profound reduction in thymic and peripheral lymphoid cellularity. Analyses of lymphoid progenitor populations in IL-7R-deficient mice define precisely those developmental stages affected by the mutation and reveal a critical role for IL-7R during early lymphoid development. Significantly, these studies indicate that the phase of thymocyte expansion occurring before the onset of T cell receptor gene rearrangement is critically dependent upon, and mediated by the high affinity receptor for IL-7.
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            Origin, homeostasis and function of Langerhans cells and other langerin-expressing dendritic cells.

            Langerhans cells (LCs) are a specialized subset of dendritic cells (DCs) that populate the epidermal layer of the skin. Langerin is a lectin that serves as a valuable marker for LCs in mice and humans. In recent years, new mouse models have led to the identification of other langerin(+) DC subsets that are not present in the epidermis, including a subset of DCs that is found in most non-lymphoid tissues. In this Review we describe new developments in the understanding of the biology of LCs and other langerin(+) DCs and discuss the challenges that remain in identifying the role of different DC subsets in tissue immunity.
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              Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation.

              The role of Notch signaling in growth/differentiation control of mammalian epithelial cells is still poorly defined. We show that keratinocyte-specific deletion of the Notch1 gene results in marked epidermal hyperplasia and deregulated expression of multiple differentiation markers. In differentiating primary keratinocytes in vitro endogenous Notch1 is required for induction of p21WAF1/Cip1 expression, and activated Notch1 causes growth suppression by inducing p21WAF1/Cip1 expression. Activated Notch1 also induces expression of 'early' differentiation markers, while suppressing the late markers. Induction of p21WAF1/Cip1 expression and early differentiation markers occur through two different mechanisms. The RBP-Jkappa protein binds directly to the endogenous p21 promoter and p21 expression is induced specifically by activated Notch1 through RBP-Jkappa-dependent transcription. Expression of early differentiation markers is RBP-Jkappa-independent and can be induced by both activated Notch1 and Notch2, as well as the highly conserved ankyrin repeat domain of the Notch1 cytoplasmic region. Thus, Notch signaling triggers two distinct pathways leading to keratinocyte growth arrest and differentiation.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2010
                18 February 2010
                : 5
                : 2
                : e9258
                Affiliations
                [1 ]Ecole Polytechnique Fédérale de Lausanne (EPFL SV ISREC), Lausanne, Switzerland
                [2 ]Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland
                [3 ]Department of Developmental Biology and Division of Dermatology, Washington University School of Medicine, St. Louis, Missouri, United States of America
                [4 ]Breast Cancer Program, Cardinal Bernardin Cancer Center, Loyola University Chicago, Chicago, Illinois, United States of America
                [5 ]Department of Biological Structure and Department of Immunology, University of Washington, Seattle, Washington, United States of America
                [6 ]Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States of America
                [7 ]Department of Dermatology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
                [8 ]Center for Biomedicine, Department of Clinical and Biological Sciences (DKBW), University of Basel, Basel, Switzerland
                Centre de Recherche Public de la Santé (CRP-Santé), Luxembourg
                Author notes

                Conceived and designed the experiments: FR. Performed the experiments: AD ADD MDP SV UK GF IF SD LLS DF. Analyzed the data: RK LM DH. Contributed reagents/materials/analysis tools: AGF WJL RK LM DH. Wrote the paper: FR.

                Article
                09-PONE-RA-14049R1
                10.1371/journal.pone.0009258
                2823782
                20174635
                f9af8e0e-6348-4673-891e-8927b78102a1
                Dumortier et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 5 November 2009
                : 27 January 2010
                Page count
                Pages: 14
                Categories
                Research Article
                Genetics and Genomics/Disease Models
                Immunology/Allergy and Hypersensitivity
                Dermatology/Atopic Dermatitis and Other Forms of Eczema

                Uncategorized
                Uncategorized

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