Desmoglein 4 is expressed in highly differentiated keratinocytes and trichocytes in human epidermis and hair follicle.

Desmosomes are critical for the tissue integrity of stratified epithelia and their appendages. Desmogleins (DSGs) and desmocollins (DSCs) are transmembrane desmosomal cadherins that interact extracellularly to link neighboring epithelial cells. We recently identified a new member of the DSG family, designated desmoglein 4, whose mutations cause hypotrichosis in human, mouse and rat. In this study, we analyzed in detail the expression domains of human desmoglein 4 protein (DSG4) in human skin relative to differentiation markers and other DSGs. Our results show that DSG4 protein is expressed in the more highly differentiated layers of the epidermis. This expression pattern in vivo is recapitulated in highly differentiated HaCaT human keratinocytes and normal human keratinocytes in vitro. In the human hair follicle, DSG4 is expressed specifically in the hair shaft cortex, the lower hair cuticle, and the upper inner root sheath (IRS) cuticle. Using a green fluorescent protein-tagged version of mouse or rat desmoglein 4 protein (Dsg4) and immuno-electron microscopy, we demonstrate that Dsg4 localizes to desmosomes both in vitro and in vivo. The highly specific expression pattern of DSG4 in the human hair follicle, combined with the phenotype of rodent models and human patients with desmoglein 4 mutations, underscores the importance of this adhesion molecule in the integrity of the hair shaft.

[1]  Walter Birchmeier,et al.  Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy , 2004, Nature Genetics.

[2]  A. Ishida-Yamamoto,et al.  Epidermal lamellar granules transport different cargoes as distinct aggregates. , 2004, The Journal of investigative dermatology.

[3]  P M Steinert,et al.  Expression of murine epidermal differentiation markers is tightly regulated by restricted extracellular calcium concentrations in vitro , 1989, The Journal of cell biology.

[4]  K. Green,et al.  The expression of desmoglein isoforms in cultured human keratinocytes is regulated by calcium, serum, and protein kinase C. , 1998, Experimental cell research.

[5]  M. H. Hardy,et al.  The secret life of the hair follicle. , 1992, Trends in genetics : TIG.

[6]  H. Bazzi,et al.  Regulation of Ultraviolet B Radiation-Mediated Activation of AP1 Signaling by Retinoids in Primary Keratinocytes , 2005, Radiation research.

[7]  H. Bazzi,et al.  Delineation of diversified desmoglein distribution in stratified squamous epithelia: implications in diseases , 2006, Experimental dermatology.

[8]  F. Watt.  Involucrin and other markers of keratinocyte terminal differentiation. , 1983, The Journal of investigative dermatology.

[9]  W. Franke,et al.  Complexity and expression patterns of the desmosomal cadherins. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[10]  R. Weichselbaum,et al.  Proteolytic activation of protein kinase C delta by an ICE‐like protease in apoptotic cells. , 1995, The EMBO journal.

[11]  J. McGrath.  Inherited disorders of desmosomes , 2005, The Australasian journal of dermatology.

[12]  G. Serre,et al.  Evidence for a role of corneodesmosin, a protein which may serve to modify desmosomes during cornification, in stratum corneum cell cohesion and desquamation , 2004, Archives of Dermatological Research.

[13]  J. Wahl.  Generation of monoclonal antibodies specific for desmoglein family members. , 2002, Hybridoma and hybridomics.

[14]  E. Fuchs,et al.  Desmoplakin is essential in epidermal sheet formation , 2001, Nature Cell Biology.

[15]  A. Christiano,et al.  A nonsense mutation in the desmoglein 1 gene underlies striate keratoderma , 2003, Experimental dermatology.

[16]  Neil Crossley,et al.  The lanceolate hair rat phenotype results from a missense mutation in a calcium coordinating site of the desmoglein 4 gene. , 2004, Genomics.

[17]  E. Lane,et al.  Mutations in the plakophilin 1 gene result in ectodermal dysplasia/skin fragility syndrome , 1997, Nature Genetics.

[18]  H. Spring,et al.  Hair keratins and hair follicle-specific epithelial keratins. , 2004, Methods in cell biology.

[19]  L Langbein,et al.  The Catalog of Human Hair Keratins , 2001, The Journal of Biological Chemistry.

[20]  J. McGrath,et al.  Human hair abnormalities resulting from inherited desmosome gene mutations. , 2005, The Keio journal of medicine.

[21]  D. Kelsell,et al.  Recessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma. , 2000, Human molecular genetics.

[22]  T. Kurtz,et al.  A spontaneous mutation in the desmoglein 4 gene underlies hypotrichosis in a new lanceolate hair rat model. , 2004, Differentiation; research in biological diversity.

[23]  J. Ott,et al.  Desmoglein 4 in Hair Follicle Differentiation and Epidermal Adhesion Evidence from Inherited Hypotrichosis and Acquired Pemphigus Vulgaris , 2003, Cell.

[24]  H. Green,et al.  Seria cultivation of strains of human epidemal keratinocytes: the formation keratinizin colonies from single cell is , 1975, Cell.

[25]  R Kemler,et al.  Embryonic heart and skin defects in mice lacking plakoglobin. , 1996, Developmental biology.

[26]  E. Fuchs,et al.  Desmoplakin Is Required Early in Development for Assembly of Desmosomes and Cytoskeletal Linkage , 1998, The Journal of cell biology.

[27]  H. Bazzi,et al.  Intragenic deletion in the Desmoglein 4 gene underlies the skin phenotype in the Iffa Credo "hairless" rat. , 2004, Differentiation; research in biological diversity.

[28]  Kathleen J. Green,et al.  Are desmosomes more than tethers for intermediate filaments? , 2000, Nature Reviews Molecular Cell Biology.

[29]  S. Leal,et al.  A recurrent intragenic deletion mutation in DSG4 gene in three Pakistani families with autosomal recessive hypotrichosis. , 2004, The Journal of investigative dermatology.

[30]  V. Mils,et al.  The expression of desmosomal and corneodesmosomal antigens shows specific variations during the terminal differentiation of epidermis and hair follicle epithelia. , 1992, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[31]  S. Millar,et al.  Molecular mechanisms regulating hair follicle development. , 2002, The Journal of investigative dermatology.

[32]  U. Nuber,et al.  Desmosomes and cytoskeletal architecture in epithelial differentiation: cell type-specific plaque components and intermediate filament anchorage. , 1994, European journal of cell biology.

[33]  Stephen R. Martin,et al.  Molecular interactions between desmosomal cadherins. , 2002, The Biochemical journal.

[34]  A. Crosby,et al.  Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease) , 2000, The Lancet.

[35]  H. Kurzen,et al.  Compositionally different desmosomes in the various compartments of the human hair follicle. , 1998, Differentiation; research in biological diversity.

[36]  S. Troyanovsky,et al.  Direct Ca2+-dependent Heterophilic Interaction between Desmosomal Cadherins, Desmoglein and Desmocollin, Contributes to Cell–Cell Adhesion , 1997, The Journal of cell biology.

[37]  K. Green,et al.  Cadherin function: Breaking the barrier , 2001, Current Biology.

[38]  B. Nickoloff,et al.  Protein Kinase Cδ Is Activated by Caspase-dependent Proteolysis during Ultraviolet Radiation-induced Apoptosis of Human Keratinocytes* , 1998, The Journal of Biological Chemistry.

[39]  Hong Wu,et al.  Desmoglein isotype expression in the hair follicle and its cysts correlates with type of keratinization and degree of differentiation. , 2003, The Journal of investigative dermatology.

[40]  A. Christiano,et al.  A recurrent intragenic deletion in the desmoglein 4 gene underlies localized autosomal recessive hypotrichosis. , 2004, The Journal of investigative dermatology.

[41]  H. Bazzi,et al.  A missense mutation in the cadherin interaction site of the desmoglein 4 gene underlies localized autosomal recessive hypotrichosis. , 2005, The Journal of investigative dermatology.

[42]  R. Windoffer,et al.  Loss of desmoglein 2 suggests essential functions for early embryonic development and proliferation of embryonal stem cells. , 2002, European journal of cell biology.

[43]  J. Schweizer,et al.  Keratins of the human hair follicle. , 2005, International review of cytology.

[44]  R. Porter,et al.  Functional analysis of keratin components in the mouse hair follicle inner root sheath , 2004, The British journal of dermatology.

[45]  R. Paus,et al.  Molecular principles of hair follicle induction and morphogenesis , 2005, BioEssays : news and reviews in molecular, cellular and developmental biology.

[46]  S. Cichon,et al.  Hypotrichosis simplex of the scalp is associated with nonsense mutations in CDSN encoding corneodesmosin , 2003, Nature Genetics.

[47]  K. Green,et al.  Regulation of desmosome assembly and adhesion. , 2004, Seminars in cell & developmental biology.

[48]  H. Green,et al.  Formation of a keratinizing epithelium in culture by a cloned cell line derived from a teratoma , 1975, Cell.