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Targeted Deletion of the Murine Corneodesmosin Gene Delineates Its Essential Role in Skin and Hair Physiology

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Targeted Deletion of the Murine Corneodesmosin Gene Delineates Its Essential Role in Skin and Hair Physiology

Mitsuru Matsumoto et al. Proc Natl Acad Sci U S A.

Abstract

Controlled proteolytic degradation of specialized junctional structures, corneodesmosomes, by epidermal proteases is an essential process for physiological desquamation of the skin. Corneodesmosin (CDSN) is an extracellular component of corneodesmosomes and, although considerable debate still exists, genetic studies have suggested that the CDSN gene in the major psoriasis-susceptibility locus (PSORS1) may be responsible for susceptibility to psoriasis, a human skin disorder characterized by excessive growth and aberrant differentiation of keratinocytes. CDSN is also expressed in the inner root sheath of hair follicles, and a heterozygous nonsense mutation of the CDSN gene in humans is associated with scalp-specific hair loss of poorly defined etiology. Here, we have investigated the pathogenetic roles of CDSN loss of function in the development of skin diseases by generating a mouse strain with targeted deletion of the Cdsn gene. Cdsn-deficient mouse skin showed detachment of the stratum corneum from the underlying granular layer and/or detachment within the upper granular layers due to the disrupted integrity of the corneodesmosomes. When grafted onto immunodeficient mice, Cdsn-deficient skin showed rapid hair loss together with epidermal abnormalities resembling psoriasis. These results underscore the essential roles of CDSN in hair physiology and suggest functional relevance of CDSN gene polymorphisms to psoriasis susceptibility.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Cdsn deficiency results in stratum corneum detachment due to defective desmosome formation. (A) Macroscopic appearance of formalin-fixed Cdsn-deficient newborn mouse with skin erosions on the limbs. (B) Loss of upper epidermis due to detachment of the stratum corneum from the underlying granular layer and/or within the upper granular layers in Cdsn-deficient mouse epidermis. Dilation of capillaries beneath the affected epidermis was also noted (arrows). (Scale bar: 100 μm.) (C) Electron density of each corneodesmosome from Cdsn-deficient mice (Lower Left, arrowhead) was markedly lower than that in wild-type mice (Upper Left, arrowheads); areas included in Fig. S2B are outlined. In contrast, formation of cornified cell envelopes (arrows) was indistinguishable between wild-type and Cdsn-deficient mice. (Right) Higher magnification of the outlined areas shown in Left. (Scale bars: 100 nm).
Fig. 2.
Fig. 2.
Abnormal hair growth from grafted Cdsn-deficient mouse skin. Embryonic skin obtained from the trunks of wild-type mice (uppermost row), heterozygous Cdsn-deficient mice (second row from top), and homozygous Cdsn-deficient mice (third row from top) was grafted onto the backs of nude mice. Gross appearance of the grafted skins 2 weeks (Left) and 4 weeks (Right) after transplantation. Thin and slightly curly hairs from skin of homozygous Cdsn-deficient mice at 2 and 4 weeks after transplantation are shown from different angles bottom most row. Representative results of one mouse for each group examined (wild-type, n = 2; heterozygous Cdsn-deficient, n = 4; homozygous Cdsn-deficient, n = 3) are shown.
Fig. 3.
Fig. 3.
Psoriasis-like skin abnormalities in grafted skin from Cdsn-deficient mice. (A) H&E staining of skin from control mice (Left) and Cdsn-deficient mice (Right) 4 weeks after grafting onto nude mice. Hyperkeratosis, parakeratosis, and marked acanthosis with structures similar to elongated rete ridges were observed in grafted Cdsn-deficient mouse skin; also note that sebaceous glands are rarely evident. (Scale bars: 300 μm.) (B) Subcorneal and intracorneal pustules with neutrophil infiltration (arrows). (Scale bar: 100 μm.) (C) Aberrant hair shafts engulfed in rete ridge-like structures (arrows). (Scale bar: 200 μm.)
Fig. 4.
Fig. 4.
Psoriasis-like skin phenotypes in grafted Cdsn-deficient mouse skin. (A) Many abnormal cellular structures including lipid droplets (L) and remnants of nuclei and organelles (arrows) were observed in the stratum corneum of grafts from Cdsn-deficient mice (Right). Keratohyalin granules (*, Left) were reduced in grafted skin from Cdsn-deficient mice compared with those in grafted skin from wild-type mice. Nu, nucleus. (B) Electron density of each corneodesmosome in grafted skin from Cdsn-deficient mice (Right, arrowhead) was markedly lower than that in grafted skin from wild-type mice (Left, arrowheads). Formation of cornified cell envelopes was also defective in grafted skin from Cdsn-deficient mice (Right, arrows).

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