Knocking-in the R142C mutation in transglutaminase 1 disrupts the stratum corneum barrier and postnatal survival of mice

Nakagawa, Noboru; Yamamoto, Masaaki; Imai, Yasutomo; Sakaguchi, Yoshiko; Takami, Takeshi; Ohta, Nobuhiro; Yagi, Naoto; Hatta, Ichiro; Hitomi, Kiyotaka; Tajima, Toshihiro; Takeda, Junji; Tsuda, Tatsuya; Matsuki, Masato; Yamanishi, Kiyofumi

doi:10.1016/j.jdermsci.2011.12.011

Cited by 17 publications

(16 citation statements)

References 35 publications

(48 reference statements)

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“…Shortly after birth, the skin of Pnpla1 −/− mice turned dry and wrinkled, and most of the Pnpla1 −/− mice showed signs of a necrotic tail tip (Figure 1a). Similar to mutant mice suffering from other genetic forms of ichthyosis (Herrmann et al, 2003; Nakagawa et al, 2012; Radner et al, 2010; Vasireddy et al, 2007), newborn Pnpla1 −/− mice were less active, markedly smaller, and weighed significantly less than their wild-type and heterozygous littermates (Supplementary Table S1 online). Notably, all of the investigated newborn Pnpla1 −/− mice died prematurely within 12 hours after birth.…”

Section: Resultsmentioning

confidence: 75%

PNPLA1 Deficiency in Mice and Humans Leads to a Defect in the Synthesis of Omega-O-Acylceramides

Grond

Eichmann

Dubrac

et al. 2017

Journal of Investigative Dermatology

103

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Mutations in PNPLA1 have been identified as causative for autosomal recessive congenital ichthyosis in humans and dogs. So far, the underlying molecular mechanisms are unknown. In this study, we generated and characterized PNPLA1-deficient mice and found that PNPLA1 is crucial for epidermal sphingolipid synthesis. The absence of functional PNPLA1 in mice impaired the formation of omega-O-acylceramides and led to an accumulation of nonesterified omega-hydroxy-ceramides. As a consequence, PNPLA1-deficient mice lacked a functional corneocyte-bound lipid envelope leading to a severe skin barrier defect and premature death of newborn animals. Functional analyses of differentiated keratinocytes from a patient with mutated PNPLA1 demonstrated an identical defect in omega-O-acylceramide synthesis in human cells, indicating that PNPLA1 function is conserved among mammals and indispensable for normal skin physiology. Notably, topical application of epidermal lipids from wild-type onto Pnpla1-mutant mice promoted rebuilding of the corneocyte-bound lipid envelope, indicating that supplementation of ichthyotic skin with omega-O-acylceramides might be a therapeutic approach for the treatment of skin symptoms in individuals affected by omega-O-acylceramide deficiency.

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Section: Resultsmentioning

confidence: 75%

PNPLA1 Deficiency in Mice and Humans Leads to a Defect in the Synthesis of Omega-O-Acylceramides

Grond

Eichmann

Dubrac

et al. 2017

Journal of Investigative Dermatology

103

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“…ichthyin is a predicted transmembrane protein with undetermined function. TGM-1 cross-links the proteins forming the corneocyte envelope (CE), and is also implicated through in vitro studies and a knock-in mouse mutation in catalyzing the covalent bond between ω-hydroxy-acyl ceramides and the CE, forming the CLE [25, 26], (albeit with human studies showing that lamellar ichthyoses due to mutations in this isozyme have a normal CLE) [27]. The fact that inactivating mutations in all of these genes produce related skin phenotypes supports the idea that they are elements of the same physiological process.…”

Section: Barrier Genes and Ichthyosismentioning

confidence: 99%

The importance of the lipoxygenase-hepoxilin pathway in the mammalian epidermal barrier

Muñoz‐Garcia

Thomas

Keeney

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

104

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Summary This review covers the background to discovery of the two key lipoxygenases (LOX) involved in epidermal barrier function, 12R-LOX and eLOX3, and our current views on their functioning. In the outer epidermis, their consecutive actions oxidize linoleic acid esterified in ω-hydroxy-ceramide to a hepoxilin-related derivative. The relevant background to hepoxilin and trioxilin biochemistry is briefly reviewed. We outline the evidence that linoleate in the ceramide is the natural substrate of the two LOX enzymes and our proposal for its importance in construction of the epidermal water barrier. Our hypothesis is that the oxidation promotes hydrolysis of the oxidized linoleate moiety from the ceramide. The resulting free ω-hydroxyl of the ω-hydroxyceramide is covalently bound to proteins on the surface of the corneocytes to form the corneocyte lipid envelope, a key barrier component. Understanding the role of the LOX enzymes and their hepoxilin products should provide rational approaches to ameliorative therapy for a number of the congenital ichthyoses involving compromised barrier function.

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“…The in situ skin permeability assay with toluidine blue was performed as described previously (18, 19). In brief, anesthetized wild type mice and Tg(+) mice prior to developing clinical AD lesions were shaved and rinsed in PBS.…”

Section: Methodsmentioning

confidence: 99%

Expression of IL-22 in the Skin Causes Th2-Biased Immunity, Epidermal Barrier Dysfunction, and Pruritus via Stimulating Epithelial Th2 Cytokines and the GRP Pathway

Lou

Choi

et al. 2017

The Journal of Immunology

105

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Increased expression of Th22 cytokine IL-22 is a characteristic finding in atopic dermatitis (AD). However, the specific role of IL-22 in the pathogenesis of AD in vivo has yet to be elucidated. Consistent with observations in human AD, IL-22 was significantly increased in the AD skin of mice after epicutaneous sensitization to house dust mite allergen. Utilizing a skin-specific inducible transgenic system, we show here that expression of IL-22 in the skin of mice caused an AD-like phenotype characterized by chronic pruritic dermatitis associated with Th2-biased local and systemic immune responses, down-regulation of Epidermal Differentiation Complex genes and enhanced dermatitis upon epicutaneous allergen exposure. IL-22 potently induced the expression of gastrin-releasing peptide (GRP), a neuropeptide pruritogen, in dermal immune cells and sensory afferents and in their skin-innervating sensory neurons. IL-22 also differentially up-regulated the expression of GRP receptor (GRPR) on keratinocytes of AD skin. The number of GRP+ cells in the skin correlated with the AD severity and the intensity of pruritus. IL-22 directly upregulated the expression of epithelial-derived type 2 cytokines (TSLP and IL-33) and GRP in primary keratinocytes. Furthermore, GRP not only strongly induced TSLP but also increased the expression IL-33 and GRPR synergistically with IL-22. Importantly, we found that the expression of GRP was strikingly increased in the skin of patients with AD. These results indicate that IL-22 plays important pathogenic roles in the initiation and development of AD, in part through inducing keratinocyte production of type 2 cytokines and activation of the GRP/GRPR pathway.

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Knocking-in the R142C mutation in transglutaminase 1 disrupts the stratum corneum barrier and postnatal survival of mice

Cited by 17 publications

References 35 publications

PNPLA1 Deficiency in Mice and Humans Leads to a Defect in the Synthesis of Omega-O-Acylceramides

PNPLA1 Deficiency in Mice and Humans Leads to a Defect in the Synthesis of Omega-O-Acylceramides

The importance of the lipoxygenase-hepoxilin pathway in the mammalian epidermal barrier

Expression of IL-22 in the Skin Causes Th2-Biased Immunity, Epidermal Barrier Dysfunction, and Pruritus via Stimulating Epithelial Th2 Cytokines and the GRP Pathway

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