Loss of epidermal Evi/Wls results in a phenotype resembling psoriasiform dermatitis

Augustin, Iris; Gross, Julia Christina; Baumann, D; Korn, Claudia; Kerr, Gráinne; Grigoryan, Tamara; Mauch, Cornelia; Birchmeier, Walter; Boutros, Michael

doi:10.1084/jem.20121871

Cited by 51 publications

(21 citation statements)

References 66 publications

(63 reference statements)

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“…Instead, these transgenic mice displayed impaired hair follicle development. In another study, the expression of Evi, which encodes the Wnt cargo receptor and the knockout of which would cause deficient Wnt secretion, was found to be downregulated in human psoriatic skin biopsies (54). In the same study, the epidermal conditional knockout of this gene led to the development of an inflammatory skin phenotype and loss of hair.…”

Section: Discussionmentioning

confidence: 88%

Epigenetic Downregulation of SFRP4 Contributes to Epidermal Hyperplasia in Psoriasis

Bai

Liu

et al. 2015

The Journal of Immunology

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Psoriasis is a chronic recurrent inflammatory skin disorder characterized by the dysregulated cross-talk between epidermal keratinocytes and immune cells, leading to keratinocyte hyperproliferation. Several studies demonstrated that Wnt pathway genes were differentially expressed in psoriatic plaques and likely were involved in the pathophysiology of disease. However, the molecular mechanisms underlying Wnt signaling regulation in epidermal hyperplasia in psoriasis remain largely unknown. We report that the expression of secreted frizzled-related protein (SFRP) 4, a negative regulator of the Wnt signaling pathway, was diminished in lesional skin of mouse models and patients with psoriasis. SFRP4 directly inhibited excessive keratinocyte proliferation evoked by proinflammatory cytokines in vitro. Pharmacological inhibition of Wnt signaling or intradermal injection of SFRP4 decreased the severity of the psoriasiform skin phenotype in vivo, including decreased acanthosis and reduced leukocyte infiltration. Mechanistically, we identified that aberrant promoter methylation resulted in epigenetic downregulation of SFRP4 in inflamed skin of patients with psoriasis and in the IL-23–induced mouse model. Our findings suggest that this epigenetic event is critically involved in the pathogenesis of psoriasis, and the downregulation of SFRP4 by CpG island methylation is one possible mechanism contributing to the hyperplasia of epidermis in the disease.

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Section: Discussionmentioning

confidence: 88%

Epigenetic Downregulation of SFRP4 Contributes to Epidermal Hyperplasia in Psoriasis

Bai

Liu

et al. 2015

The Journal of Immunology

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“…Mice with loxP-flanked alleles encoding Gpr177 (Gpr177 fl/fl ) were described earlier (24). We crossed these mice to FoxN1…”

Section: Animalsmentioning

confidence: 99%

“…2A. FoxN1-Gpr177 mice are viable and, with the exception of a mild hair loss (presumably due to FoxN1 promoter activity and concomitant loss of Gpr177 in keratinocytes), show no developmental defects or overt health problems (24). Unless otherwise stated, we used mice of both sexes at the age of 4-6 wk.…”

Section: Loss Of Wnt Secretion By Tecs Impairs Thymus Developmentmentioning

confidence: 99%

“…The Wnt cargo receptor Evi/Wls/Gpr177 is required for the secretion of Wnt ligands (22,23). We crossed Gpr177 flox/flox (24) mice to FoxN1-Cre mice to obtain a mouse line in which Gpr177 knockout is targeted to thymic epithelial cells (termed FoxN1-Gpr177). We show in this article that TECs constitute a nonredundant source of Wnt ligands in the thymus, which plays an essential role in the production of T cells.…”

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confidence: 99%

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Thymic Epithelial Cells Are a Nonredundant Source of Wnt Ligands for Thymus Development

Brunk

Augustin

Meister

et al. 2015

The Journal of Immunology

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Wnt signaling has been implicated in T cell development. However, it remained unclear which cell type is the major source of Wnt ligands and to what extent thymic epithelial cell (TEC) development is dependent on Wnt signaling. In this study, we analyzed the role of Wnt ligands provided by TECs for the development of T cells and TECs without manipulating the intracellular Wnt signaling machinery in either cell type. To this end, we used conditional knockout mice (FoxN1-Gpr177) in which TECs are unable to secrete Wnt ligands. Gpr177 (Evi/Wls) is a Wnt-specific cargo receptor that is required for the secretion of Wnt ligands. We found that TECs are the main source of Wnt ligands in the thymus, which serves a nonredundant role, and lack of TEC-provided Wnt ligands led to thymic hypotrophy, as well as a reduced peripheral T cell pool. Despite being reduced in numbers, T cells that developed in the absence of TEC-secreted Wnt ligands were functionally competent, and the subset composition of the peripheral T cell pool was not affected. Thus, our data suggest that T cell development is not directly dependent on TEC-provided Wnt ligands. Rather, TEC-secreted Wnt ligands are essential for normal thymus development and normal peripheral T cell frequencies but are dispensable for T cell function in the periphery.

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“…Floxed Evi mice (Evi fl/fl ) were generated as described previously (Augustin et al, 2013). Briefly, the Evi locus was targeted by flanking exon 3 of the Evi gene by loxP sites.…”

Section: Micementioning

confidence: 99%

Endothelial cell-derived non-canonical Wnt ligands control vascular pruning in angiogenesis

Korn

Scholz

et al. 2014

Journal of Cell Science

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Multiple cell types involved in the regulation of angiogenesis express Wnt ligands. Although β-catenin dependent and independent Wnt signaling pathways have been shown to control angiogenesis, the contribution of individual cell types to activate these downstream pathways in endothelial cells (ECs) during blood vessel formation is still elusive. To investigate the role of ECs in contributing Wnt ligands for regulation of blood vessel formation, we conditionally deleted the Wnt secretion factor Evi in mouse ECs (Evi-ECKO). Evi-ECKO mice showed decreased microvessel density during physiological and pathological angiogenesis in the postnatal retina and in tumors, respectively. The reduced microvessel density resulted from increased vessel regression accompanied by decreased EC survival and proliferation. Concomitantly, survival-related genes were downregulated and cell cycle arrest-and apoptosis-inducing genes were upregulated. EVI silencing in cultured HUVECs showed similar target gene regulation, supporting a mechanism of EC-derived Wnt ligands in controlling EC function. ECs preferentially expressed non-canonical Wnt ligands and canonical target gene expression was unaffected in Evi-ECKO mice. Furthermore, the reduced vascularization of Matrigel plugs in Evi-ECKO mice could be rescued by introduction of non-canonical Wnt5a. Treatment of mouse pups with the non-canonical Wnt inhibitor TNP470 resulted in increased vessel regression accompanied by decreased EC proliferation, thus mimicking the proliferation-dependent Evi-ECKO remodeling phenotype. Taken together, this study identified EC-derived non-canonical Wnt ligands as regulators of EC survival, proliferation and subsequent vascular pruning during developmental and pathological angiogenesis.

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Loss of epidermal Evi/Wls results in a phenotype resembling psoriasiform dermatitis

Abstract: The Wnt cargo receptor Evi maintains normal skin homeostasis and barrier function via Wnt secretion in the epidermis.

Cited by 51 publications

References 66 publications

Epigenetic Downregulation of SFRP4 Contributes to Epidermal Hyperplasia in Psoriasis

Epigenetic Downregulation of SFRP4 Contributes to Epidermal Hyperplasia in Psoriasis

Thymic Epithelial Cells Are a Nonredundant Source of Wnt Ligands for Thymus Development

Endothelial cell-derived non-canonical Wnt ligands control vascular pruning in angiogenesis

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