Development of ichthyosiform skin compensates for defective permeability barrier function in mice lacking transglutaminase 1

Kuramoto, Nobuyuki; Tajima, Toshihiro; Takami, Takeshi; Matsuki, Masato; Morioka, Hiroyuki; Robinson, John M.; Yamanishi, Kiyofumi

doi:10.1172/jci13563

Cited by 56 publications

(40 citation statements)

References 48 publications

(14 reference statements)

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“…Transepidermal water loss (TEWL) of affected skin in 10-day-old St14 hypo/– mice is normal (data not shown), consistent with the normal TEWL and increased scale demonstrated in grafted skin from TGase –/– mice, another adult animal model of impaired skin barrier (Kuramoto et al ., 2002). …”

Section: Resultssupporting

confidence: 70%

Matriptase-Deficient Mice Exhibit Ichthyotic Skin with a Selective Shift in Skin Microbiota

Scharschmidt

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Grice

et al. 2009

Journal of Investigative Dermatology

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Suppressor of tumorigenicity 14 (St14) encodes matriptase, a serine protease, which regulates processing of profilaggrin to filaggin in vivo. Here, we report that transgenic mice with 1% of wild-type St14 levels (St14hypo/–) display aberrant processing of profilaggrin and model human ichthyotic skin phenotypes. Scaling of the skin appears at 1 week of age with underlying epidermal acanthosis and orthohyperkeratosis as well as a CD4+ T-cell dermal infiltrate. Upregulation of antimicrobial peptides occurs when challenged by exposure to the postnatal environment. Direct genomic sequencing of bacterial 16S rRNA genes to query microbial diversity identifies a significant shift in both phylogeny and community structure between St14hypo/– mice and control littermates. St14hypo/– mice have a selective shift in resident skin microbiota with a decrease of the dominant genus of skin bacteria, Pseudomonas and an accompanying increase of Corynebacterium and Streptococcus. St14hypo/– mice provide early evidence that the cutaneous microbiome can be specifically altered by genetic state, which may play an important role in modulating skin disease.

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Section: Resultssupporting

confidence: 70%

Matriptase-Deficient Mice Exhibit Ichthyotic Skin with a Selective Shift in Skin Microbiota

Scharschmidt

List

Grice

et al. 2009

Journal of Investigative Dermatology

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“…After birth, the reactive epidermal hyperplasia masks the physical consequences of skin-barrier impairments (i.e. dye penetration or transepidermal water loss) to ensure survival in terrestrial life (Kuramoto et al, 2002). Nonetheless, thymic stromal lymphopoietin (TSLP) and antimicrobial peptide overexpression can serve as reliable biomarkers for postnatal barrier impairments (Aberg et al, 2008; Demehri et al, 2008; Kuramoto et al, 2002).…”

Section: Resultsmentioning

confidence: 99%

“…dye penetration or transepidermal water loss) to ensure survival in terrestrial life (Kuramoto et al, 2002). Nonetheless, thymic stromal lymphopoietin (TSLP) and antimicrobial peptide overexpression can serve as reliable biomarkers for postnatal barrier impairments (Aberg et al, 2008; Demehri et al, 2008; Kuramoto et al, 2002). Based on this criteria, a mild barrier defect is also detectable in Msx2-N1CKO skin at P9 (Figure S6A; (Demehri et al, 2008)).…”

Section: Resultsmentioning

confidence: 99%

Epidermal Notch1 Loss Promotes Skin Tumorigenesis by Impacting the Stromal Microenvironment

2009

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Summary Notch1 is a proto-oncogene in several organs. In the skin, however, Notch1 deletion leads to tumor formation, suggesting that Notch1 is a “tumor suppressor” within this context. Here we demonstrate that, unlike classical tumor suppressors, Notch1 loss in epidermal keratinocytes promotes tumorigenesis non-cell autonomously by impairing skin-barrier integrity and creating a wound-like microenvironment in the skin. Using mice with a chimeric pattern of Notch1 deletion, we determined that Notch1-expressing keratinocytes in this microenvironment readily formed papillomas, showing that Notch1 was insufficient to suppress this tumor-promoting effect. Accordingly, loss of other Notch paralogs that impaired the skin barrier also predisposed Notch1-expressing skin to tumorigenesis, demonstrating that the tumor-promoting effect of Notch1 loss involves a crosstalk between barrier-defective epidermis and its stroma. Significance In contrast to the current dogma, we demonstrate unequivocally that the non-cell autonomous consequences of defective barrier formation are responsible for the tumor-promoting effects of Notch1 loss in mouse skin. Thus, individuals with sub-acute skin-barrier defects may also be prone to carcinogenesis upon exposure to initiating carcinogens like UV rays. As Notch1 deletion in skin tumors enhanced their progression to invasive arcinomas, patients with benign hyperplasic skin lesions receiving γ-secretase inhibitor therapy may, therefore, be at additional risk. More broadly, given that chronic injury causatively effects the development of several human carcinomas, Notch1-deficient mice with mild skin-barrier defects can serve as an experimental model in which to study the tumor-promoting elements of chronic injury/wound and develop relevant therapies.

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“…The importance of the envelope is demonstrated by neonatal lethality due to barrier function failure in mice null for a key transglutaminase enzyme needed for cross‐linking these stratum corneum proteins and lipids (see Fig. 2 inset; Kuramoto et al. 2002).…”

Section: Epidermis As a Structural Barrier Organmentioning

confidence: 99%

Covering the limb – formation of the integument

2003

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An organism's outermost covering, the integument, has evolved to fulfil a diverse range of functions. Skin provides a physical barrier, an environment for immunological surveillance, and also performs a range of sensory, thermoregulatory and biosynthetic functions. Examination of the skin of limb digits reveals a range of skin types including the thickened hairless epidermis of the toe pads (palmar or plantar epidermis) and thinner epidermis between the hair follicles (interfollicular epidermis) of hairy skin. An important developmental function of skin is to give rise to a diverse group of appendages including hair follicles, with associated sebaceous glands (or feathers and scales in chick), eccrine sweat glands and the nail. A key question is how does this morphological variety arise from the single-layered epithelium covering embryonic limb buds? This review will attempt to address this question by linking the extensive morphological /anatomical data on maturation of epidermis and its appendages with (1) current research into the range, plasticity and location of the putative epidermal stems cells; (2) molecular/microenvironmental regulation of epidermal stem cell lineages and lineage choice; and (3) regulation of the differentiation pathways, focusing on differentiation of the interfollicular epidermis.Key words appendages; cell lineages; ectoderm, skin barrier; skin development; terminal differentiation. Epidermis as a structural barrier organNormal adult skin comprises a thin surface epidermis nourished and maintained by a thicker dermis. Epidermis of the limb gives rise to a range of skin types (palmar, plantar and interfollicular epidermis) and varied appendages (including hair follicles, sebaceous glands, eccrine sweat glands and the nail) (Fig. 1). Epidermis' primary role is protective and it provides protection largely through construction of an elaborate and highly organized outer surface, the stratum corneum. Stratum corneum is the primary interface and barrier between an organism and its outer environment and acts to prevent desiccation, toxin entry and microbial infection.A key feature of this protective outer layer is that it is continually shed and replenished by underlying keratinocytes, so that damaged, infected or contaminated cells are removed from the body and the barrier is maintained. The stem cells necessary for maintenance of this cycling structure are located in the basal stratum of epidermis ( Fig. 2) and in specialized compartments of skin appendages like hair follicles (see reviews by Fuchs & Raghavan, 2002;Watt, 2002). Proliferative keratinocytes (transit or transiently amplifying cells) derived from these stem cells also reside in this basal layer (see Stratum corneum consists of anucleate, flattened keratinocytes embedded in a lipid matrix ( Fig. 2; reviewed by Kalinin et al. 2001 The basement membrane separates the dermis (primarily consisting of fibroblasts, elastin and collagen) and the overlying epidermis. The epidermis comprises four distinct layers, basal, spino...

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Development of ichthyosiform skin compensates for defective permeability barrier function in mice lacking transglutaminase 1

Cited by 56 publications

References 48 publications

Matriptase-Deficient Mice Exhibit Ichthyotic Skin with a Selective Shift in Skin Microbiota

Matriptase-Deficient Mice Exhibit Ichthyotic Skin with a Selective Shift in Skin Microbiota

Epidermal Notch1 Loss Promotes Skin Tumorigenesis by Impacting the Stromal Microenvironment

Covering the limb – formation of the integument

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