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  4. Atopic dermatitis-like disease and associated lethal myeloproliferative disorder arise from loss of notch signaling in the murine skin
 
research article

Atopic dermatitis-like disease and associated lethal myeloproliferative disorder arise from loss of notch signaling in the murine skin

Dumortier, Alexis
•
Durham, A. D.
•
Di Piazza, M.
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2010
Plos One

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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Type
research article
DOI
10.1371/journal.pone.0009258
Web of Science ID

WOS:000274654700010

Author(s)
Dumortier, Alexis
Durham, A. D.
Di Piazza, M.
Vauclair, S.
Koch, U.  
Ferrand, G.
Ferrero, I.
Demehri, S.
Song, L. L.
Farr, A. G.
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Date Issued

2010

Publisher

Public Library of Science

Published in
Plos One
Volume

5

Issue

2

Article Number

e9258

Subjects

Thymic Stromal Lymphopoietin

•

B-Cell Development

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Human Epithelial-Cells

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T-Cell

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Stem-Cells

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In-Vitro

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Mouse Keratinocytes

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Growth-Factor

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Mice

•

Expression

Editorial or Peer reviewed

NON-REVIEWED

Written at

EPFL

EPFL units
UPRAD  
Available on Infoscience
August 23, 2010
Use this identifier to reference this record
https://infoscience.epfl.ch/handle/20.500.14299/52366
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