title: Atopic dermatitis-like disease and associated lethal myeloproliferative disorder arise from loss of Notch signaling in the murine skin.
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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  Our data demonstrate a critical role for Notch in repressing TSLP production in keratinocytes, thereby maintaining integrity of the skin and the hematopoietic system.
authors.affiliation: Ecole Polytechnique Fédérale de Lausanne (EPFL SV ISREC), Lausanne, Switzerland.
authors.forename: Alexis
authors.initials: A
authors.lastname: Dumortier
authors.forename: André-Dante
authors.initials: AD
authors.lastname: Durham
authors.forename: Matteo
authors.initials: M
authors.lastname: Di Piazza
authors.forename: Sophie
authors.initials: S
authors.lastname: Vauclair
authors.forename: Ute
authors.initials: U
authors.lastname: Koch
authors.forename: Gisèle
authors.initials: G
authors.lastname: Ferrand
authors.forename: Isabel
authors.initials: I
authors.lastname: Ferrero
authors.forename: Shadmehr
authors.initials: S
authors.lastname: Demehri
authors.forename: Lynda Li
authors.initials: LL
authors.lastname: Song
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Farr
authors.forename: Warren J
authors.initials: WJ
authors.lastname: Leonard
authors.forename: Raphael
authors.initials: R
authors.lastname: Kopan
authors.forename: Lucio
authors.initials: L
authors.lastname: Miele
authors.forename: Daniel
authors.initials: D
authors.lastname: Hohl
authors.forename: Daniela
authors.initials: D
authors.lastname: Finke
authors.forename: Freddy
authors.initials: F
authors.lastname: Radtke
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D003876:Dermatitis, Atopic / Q000235:genetics / Q000401:mortality / Q000503:physiopathology*; D005434:Flow Cytometry; D016179:Granulocyte Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007136:Immunoglobulins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D008822:Mice, Transgenic; D008954:Models, Biological; D009196:Myeloproliferative Disorders / Q000235:genetics / Q000401:mortality / Q000503:physiopathology*; D051881:Receptor, Notch1 / Q000235:genetics / Q000502:physiology; D051883:Receptor, Notch2 / Q000235:genetics / Q000502:physiology; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D012867:Skin / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D016019:Survival Analysis; D015996:Survival Rate; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D016207:Cytokines; D007136:Immunoglobulins; C497762:Notch1 protein, mouse; C497765:Notch2 protein, mouse; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D018121:Receptors, Cytokine; D051880:Receptors, Notch; C410591:Tslpr protein, mouse; D016179:Granulocyte Colony-Stimulating Factor; D000094632:Thymic Stromal Lymphopoietin