The Experts below are selected from a list of 555 Experts worldwide ranked by ideXlab platform
Guy Serre - One of the best experts on this subject based on the ideXlab platform.
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The Actin-Based Motor Myosin Vb Is Crucial to Maintain Epidermal Barrier Integrity
The Journal of investigative dermatology, 2019Co-Authors: Marie Reynier, Michel Simon, Guy Serre, Sophie Allart, Dominique Goudounèche, Alain Moga, Corinne LeprinceAbstract:Myosin Vb (Myo5b) is an unconventional myosin involved in the actin-dependent transport and tethering of intracellular organelles. In the epidermis, granular keratinocytes accumulate cytoplasmic lamellar bodies (LBs), secretory vesicles released at the junction with the stratum corneum that participate actively in the maintenance of the epidermal barrier. We have previously demonstrated that LB biogenesis is controlled by the Rab11a guanosine triphosphate hydrolase, known for its ability to recruit the Myo5b motor. In order to better characterize the molecular pathway that controls LB trafficking, we analyzed the role of F-actin and Myo5b in the epidermis. We demonstrated that LB distribution in granular keratinocytes was dependent on a dynamic F-actin cytoskeleton. Myo5b was shown to be highly expressed in granular keratinocytes and associated with Corneodesmosin-loaded LB. In reconstructed human epidermis, Myo5b silencing led to epidermal barrier defects associated with structural alterations of the stratum corneum and a reduced pool of LB showing signs of disordered maturation. Myo5b depletion also disturbed the expression and distribution of both LB cargoes and junctional components, such as claudin-1, which demonstrates its action on both LB trafficking and junctional complex composition. Together, our data reveal the essential role of Myo5b in maintaining the epidermal barrier integrity.
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Refined Immunochemical Characterization in Healthy Dog Skin of the Epidermal Cornification Proteins, Filaggrin, and Corneodesmosin.
The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society, 2018Co-Authors: Didier Pin, Marek Haftek, Guy Serre, Valérie Pendaries, Sokhna Keita Alassane, Carine Froment, Nicolas Amalric, Marie-christine Cadiergues, Emilie Vidémont, Michel SimonAbstract:Filaggrin (FLG) and Corneodesmosin (CDSN) are two key proteins of the human epidermis. FLG loss-of-function mutations are the strongest genetic risk factors for human atopic dermatitis. Studies of the epidermal distribution of canine FLG and CDSN are limited. Our aim was to better characterize the distribution of FLG and CDSN in canine skin. Using immunohistochemistry on beagle skin, we screened a series of monoclonal antibodies (mAbs) specific for human FLG and CDSN. The cross-reactive mAbs were further used using immunoelectron microscopy and Western blotting. The structure of canine CDSN and FLG was determined using publicly available databases. In the epidermis, four anti-FLG mAbs stained keratohyalin granules in the granular keratinocytes and corneocyte matrix of the lower cornified layer. In urea-extracts of dog epidermis, several bands corresponding to proFLG and FLG monomers were detected. One anti-CDSN mAb stained the cytoplasm of granular keratinocytes and cells of both the inner root sheath and medulla of hair follicles. Dog CDSN was located in lamellar bodies, in the extracellular parts of desmosomes and in corneodesmosomes. A protein of 52 kDa was immunodetected. Genomic DNA analysis revealed that the amino acid sequence and structure of canine and human CDSN were highly similar.
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DS_10.1369_0022155418798807 – Supplemental material for Refined Immunochemical Characterization in Healthy Dog Skin of the Epidermal Cornification Proteins, Filaggrin, and Corneodesmosin
2018Co-Authors: Didier Pin, Marek Haftek, Guy Serre, Valérie Pendaries, Sokhna Keita Alassane, Carine Froment, Nicolas Amalric, Marie-christine Cadiergues, Emilie Vidémont, Michel SimonAbstract:Supplemental material, DS_10.1369_0022155418798807 for Refined Immunochemical Characterization in Healthy Dog Skin of the Epidermal Cornification Proteins, Filaggrin, and Corneodesmosin by Didier Pin, Valérie Pendaries, Sokhna Keita Alassane, Carine Froment, Nicolas Amalric, Marie-Christine Cadiergues, Guy Serre, Marek Haftek, Emilie Vidémont and Michel Simon in Journal of Histochemistry & Cytochemistry
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In a three-dimensional reconstructed human epidermis filaggrin-2 is essential for proper cornification
Cell Death and Disease, 2015Co-Authors: Valérie Pendaries, Guy Serre, M. Le Lamer, Britta Hansmann, Jérémy Malaisse, Sanja Kezic, Michel SimonAbstract:Atopic dermatitis is a chronic inflammatory skin disease with defects in the epidermal barrier. In a cohort of African-American children, a FLG2 nonsense mutation has been associated with the disease. In the epidermis of European patients, the expression of filaggrin-2, the filaggrin-related protein encoded by FLG2, is decreased. To describe the function of filaggrin-2 and evaluate the impact of its deficiency, its expression was downregulated using lentivirus-mediated shRNA interference in a three-dimensional reconstructed human epidermis (RHE) model. This resulted in parakeratosis and a compact stratum corneum, presence of abnormal vesicles inside the corneocytes, increased pH and reduced amounts of free amino acids at the RHE surface, leading to increased sensitivity to UVB radiations. The expression of differentiation markers was slightly modified. However, we observed reduced proteolytic processing of Corneodesmosin, hornerin and filaggrin in parallel with reduced amounts of caspase-14 and bleomycin hydrolase. Our data demonstrated that filaggrin-2 is important for a proper cornification and a functional stratum corneum. Its downregulation in atopic patients may be involved in the disease-associated epidermis impairment.
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High TMEM45A expression is correlated to epidermal keratinization.
Experimental dermatology, 2014Co-Authors: Aurélie Hayez, Michel Simon, Marek Haftek, Guy Serre, Jérémy Malaisse, Edith Roegiers, Marie Reynier, Chantal Renard, Vincent Geenen, Catherine Lambert De RouvroitAbstract:TMEM45A (DERP7, DNAPTP4 or FLJ10134) gene, belonging to the TMEM family encoding predicted transmembrane proteins, is highly expressed in epidermal keratinocytes. To investigate the potential involvement of TMEM45A during the differentiation and keratinization processes, its expression has been characterized in normal human keratinocytes and the protein subcellular localization has been studied in this cell type, both in vitro and in vivo . TMEM45A expression is upregulated with differentiation, either induced by cultured keratinocyte confluence or enhanced Ca 2+ concentration in medium. In vivo , TMEM45A mRNA and protein are mostly found in the granular layer of the epidermis. TMEM45A expression is linked to keratinization, as accumulation of the protein is detected in native and reconstructed epidermis as well as in thymic Hassal bodies, but not in non-keratinized stratified epithelia. At the subcellular level, co-detection with ER and Golgi markers reveals that TM protein 45A is associated with the Golgi apparatus and more specifically with the trans-Golgi/trans-Golgi network in vitro and in granular layer in vivo. The protein is neither related to lysosomes nor transported within Corneodesmosin-containing lamellar bodies. These data demonstrate a strong correlation between TMEM45A expression and epidermal keratinization, indicating the relevance of this gene in this process. Abbreviations: CALN, calnexin; CDSN, Corneodesmosin; ER, endoplasmic reticulum; FLG, filaggrin; IVL, involucrin; KLK7, kallikrein 7; KRT, keratin; TM protein 45A, transmembrane protein 45A.
Michel Simon - One of the best experts on this subject based on the ideXlab platform.
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The Actin-Based Motor Myosin Vb Is Crucial to Maintain Epidermal Barrier Integrity
The Journal of investigative dermatology, 2019Co-Authors: Marie Reynier, Michel Simon, Guy Serre, Sophie Allart, Dominique Goudounèche, Alain Moga, Corinne LeprinceAbstract:Myosin Vb (Myo5b) is an unconventional myosin involved in the actin-dependent transport and tethering of intracellular organelles. In the epidermis, granular keratinocytes accumulate cytoplasmic lamellar bodies (LBs), secretory vesicles released at the junction with the stratum corneum that participate actively in the maintenance of the epidermal barrier. We have previously demonstrated that LB biogenesis is controlled by the Rab11a guanosine triphosphate hydrolase, known for its ability to recruit the Myo5b motor. In order to better characterize the molecular pathway that controls LB trafficking, we analyzed the role of F-actin and Myo5b in the epidermis. We demonstrated that LB distribution in granular keratinocytes was dependent on a dynamic F-actin cytoskeleton. Myo5b was shown to be highly expressed in granular keratinocytes and associated with Corneodesmosin-loaded LB. In reconstructed human epidermis, Myo5b silencing led to epidermal barrier defects associated with structural alterations of the stratum corneum and a reduced pool of LB showing signs of disordered maturation. Myo5b depletion also disturbed the expression and distribution of both LB cargoes and junctional components, such as claudin-1, which demonstrates its action on both LB trafficking and junctional complex composition. Together, our data reveal the essential role of Myo5b in maintaining the epidermal barrier integrity.
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Refined Immunochemical Characterization in Healthy Dog Skin of the Epidermal Cornification Proteins, Filaggrin, and Corneodesmosin.
The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society, 2018Co-Authors: Didier Pin, Marek Haftek, Guy Serre, Valérie Pendaries, Sokhna Keita Alassane, Carine Froment, Nicolas Amalric, Marie-christine Cadiergues, Emilie Vidémont, Michel SimonAbstract:Filaggrin (FLG) and Corneodesmosin (CDSN) are two key proteins of the human epidermis. FLG loss-of-function mutations are the strongest genetic risk factors for human atopic dermatitis. Studies of the epidermal distribution of canine FLG and CDSN are limited. Our aim was to better characterize the distribution of FLG and CDSN in canine skin. Using immunohistochemistry on beagle skin, we screened a series of monoclonal antibodies (mAbs) specific for human FLG and CDSN. The cross-reactive mAbs were further used using immunoelectron microscopy and Western blotting. The structure of canine CDSN and FLG was determined using publicly available databases. In the epidermis, four anti-FLG mAbs stained keratohyalin granules in the granular keratinocytes and corneocyte matrix of the lower cornified layer. In urea-extracts of dog epidermis, several bands corresponding to proFLG and FLG monomers were detected. One anti-CDSN mAb stained the cytoplasm of granular keratinocytes and cells of both the inner root sheath and medulla of hair follicles. Dog CDSN was located in lamellar bodies, in the extracellular parts of desmosomes and in corneodesmosomes. A protein of 52 kDa was immunodetected. Genomic DNA analysis revealed that the amino acid sequence and structure of canine and human CDSN were highly similar.
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DS_10.1369_0022155418798807 – Supplemental material for Refined Immunochemical Characterization in Healthy Dog Skin of the Epidermal Cornification Proteins, Filaggrin, and Corneodesmosin
2018Co-Authors: Didier Pin, Marek Haftek, Guy Serre, Valérie Pendaries, Sokhna Keita Alassane, Carine Froment, Nicolas Amalric, Marie-christine Cadiergues, Emilie Vidémont, Michel SimonAbstract:Supplemental material, DS_10.1369_0022155418798807 for Refined Immunochemical Characterization in Healthy Dog Skin of the Epidermal Cornification Proteins, Filaggrin, and Corneodesmosin by Didier Pin, Valérie Pendaries, Sokhna Keita Alassane, Carine Froment, Nicolas Amalric, Marie-Christine Cadiergues, Guy Serre, Marek Haftek, Emilie Vidémont and Michel Simon in Journal of Histochemistry & Cytochemistry
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In a three-dimensional reconstructed human epidermis filaggrin-2 is essential for proper cornification
Cell Death and Disease, 2015Co-Authors: Valérie Pendaries, Guy Serre, M. Le Lamer, Britta Hansmann, Jérémy Malaisse, Sanja Kezic, Michel SimonAbstract:Atopic dermatitis is a chronic inflammatory skin disease with defects in the epidermal barrier. In a cohort of African-American children, a FLG2 nonsense mutation has been associated with the disease. In the epidermis of European patients, the expression of filaggrin-2, the filaggrin-related protein encoded by FLG2, is decreased. To describe the function of filaggrin-2 and evaluate the impact of its deficiency, its expression was downregulated using lentivirus-mediated shRNA interference in a three-dimensional reconstructed human epidermis (RHE) model. This resulted in parakeratosis and a compact stratum corneum, presence of abnormal vesicles inside the corneocytes, increased pH and reduced amounts of free amino acids at the RHE surface, leading to increased sensitivity to UVB radiations. The expression of differentiation markers was slightly modified. However, we observed reduced proteolytic processing of Corneodesmosin, hornerin and filaggrin in parallel with reduced amounts of caspase-14 and bleomycin hydrolase. Our data demonstrated that filaggrin-2 is important for a proper cornification and a functional stratum corneum. Its downregulation in atopic patients may be involved in the disease-associated epidermis impairment.
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High TMEM45A expression is correlated to epidermal keratinization.
Experimental dermatology, 2014Co-Authors: Aurélie Hayez, Michel Simon, Marek Haftek, Guy Serre, Jérémy Malaisse, Edith Roegiers, Marie Reynier, Chantal Renard, Vincent Geenen, Catherine Lambert De RouvroitAbstract:TMEM45A (DERP7, DNAPTP4 or FLJ10134) gene, belonging to the TMEM family encoding predicted transmembrane proteins, is highly expressed in epidermal keratinocytes. To investigate the potential involvement of TMEM45A during the differentiation and keratinization processes, its expression has been characterized in normal human keratinocytes and the protein subcellular localization has been studied in this cell type, both in vitro and in vivo . TMEM45A expression is upregulated with differentiation, either induced by cultured keratinocyte confluence or enhanced Ca 2+ concentration in medium. In vivo , TMEM45A mRNA and protein are mostly found in the granular layer of the epidermis. TMEM45A expression is linked to keratinization, as accumulation of the protein is detected in native and reconstructed epidermis as well as in thymic Hassal bodies, but not in non-keratinized stratified epithelia. At the subcellular level, co-detection with ER and Golgi markers reveals that TM protein 45A is associated with the Golgi apparatus and more specifically with the trans-Golgi/trans-Golgi network in vitro and in granular layer in vivo. The protein is neither related to lysosomes nor transported within Corneodesmosin-containing lamellar bodies. These data demonstrate a strong correlation between TMEM45A expression and epidermal keratinization, indicating the relevance of this gene in this process. Abbreviations: CALN, calnexin; CDSN, Corneodesmosin; ER, endoplasmic reticulum; FLG, filaggrin; IVL, involucrin; KLK7, kallikrein 7; KRT, keratin; TM protein 45A, transmembrane protein 45A.
Nathalie Jonca - One of the best experts on this subject based on the ideXlab platform.
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Analysis of protein-protein interaction between late cornified envelope proteins and Corneodesmosin.
Experimental dermatology, 2014Co-Authors: Judith G.m. Bergboer, Nathalie Jonca, Maria G. Dulak, Ivonne M.j.j. Van Vlijmen-willems, Erwin Van Wijk, Wiljan Hendriks, Patrick L.j.m. Zeeuwen, Joost SchalkwijkAbstract:Deletion of two members of the late cornified envelope (LCE) family, LCE3B and LCE3C (LCE3C_LCE3B-del), has been identified as risk factor for psoriasis with a possible role in skin barrier function. Moreover, genetic interaction between LCE3C_LCE3B-del and HLA-C*06, located in the psoriasis susceptibility regions 4 and 1 (PSORS4 and 1), has been reported in several populations. Because of high linkage disequilibrium between the PSORS1 genes HLA-C*06 and Corneodesmosin (CDSN), both genes are potentially involved in psoriasis. As Corneodesmosin and LCE proteins are both constituents of the stratum corneum, we investigated potential direct protein-protein interactions between six LCE proteins and two Corneodesmosin sequence variants. Partial colocalization of LCE2 and CDSN was observed in normal and psoriasis skin using immunofluorescence microscopy. Co-expression of eCFP-LCE and mRFP-CDSN proteins in COS-1 cells and human adult keratinocytes, and GST pull-down results did not provide evidence for direct interactions between LCE proteins and CDSN variants.
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Identification of the first nonsense CDSN mutation with expression of a truncated protein causing peeling skin syndrome type B
The British journal of dermatology, 2013Co-Authors: A. Mallet, Nathalie Jonca, Guy Serre, Magdalini Kypriotou, K. George, Emilie A. Leclerc, Dianelys Rivero, Juliette Mazereeuw-hautier, Marcel Huber, Daniel HohlAbstract:Peeling skin disease (PSD), a generalized inflammatory form of peeling skin syndrome, is caused by autosomal recessive nonsense mutations in the Corneodesmosin gene (CDSN). To investigate a novel mutation in CDSN. A 50-year-old white woman showed widespread peeling with erythema and elevated serum IgE. DNA sequencing, immunohistochemistry, Western blot and real-time polymerase chain reaction analyses of skin biopsies were performed in order to study the genetics and to characterize the molecular profile of the disease. Histology showed hyperkeratosis and acanthosis of the epidermis, and inflammatory infiltrates in the dermis. DNA sequencing revealed a homozygous mutation leading to a premature termination codon in CDSN: p.Gly142*. Protein analyses showed reduced expression of a 16-kDa Corneodesmosin mutant in the upper epidermal layers, whereas the full-length protein was absent. These results are interesting regarding the genotype-phenotype correlations in diseases caused by CDSN mutations. The PSD-causing CDSN mutations identified heretofore result in total Corneodesmosin loss, suggesting that PSD is due to full Corneodesmosin deficiency. Here, we show for the first time that a mutant Corneodesmosin can be stably expressed in some patients with PSD, and that this truncated protein is very probably nonfunctional. © 2013 British Association of Dermatologists.
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Expression of LRP1 in human epidermis.
2013Co-Authors: Marie-florence Galliano, Nathalie Jonca, Guy Serre, Eve Toulza, Steven L. Gonias, Marina GuerrinAbstract:Immunohistochemistry and immunofluorescence analyses on skin samples in the presence of 8G1 (A, B) or 5A6 mAbs (C–G). A, the α chain of LRP1 labeling shows weak cytoplasmic staining in the spinous layers while it appears to locate at the periphery in the upper layers of the epidermis. B, using immunofluorescence, the α chain of LRP1 labeling is detected in the granular layer of epidermis. The dermis was also labeled. C and D, the β chain of LRP1 is associated within the granular layer of epidermis. The dermis was positive. A, C, original magnification×200. B, D, bar, 15 µm. E–G, Double labeling for LRP1 and Corneodesmosin (E), involucrin (F) and desmocollin (G). LRP1 does not colocalize with Corneodesmosin or involucrin but colocalizes with desmocollin 1 within keratinocytes of the granular layer. D, E, F, nuclei were counterstained with TOTO. H, Biochemical analysis of LRP1 expression. The α chain and β chain of LRP1 were detected in RAW cells and in human epidermis by immunoprecipitation. Lysates from RAW cells or 300 µg of epidermal proteins (epid.) were incubated with 8G1 or 5A6 mAbs or without antibody (−). Standard immunoprecipitations were then applied. The blots were probed with the same antibodies. Under non-reducing conditions, the dimers formed by IgH and IgL chains were detected.
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Corneodesmosomes and Corneodesmosin: from the stratum corneum cohesion to the pathophysiology of genodermatoses.
European journal of dermatology : EJD, 2011Co-Authors: Nathalie Jonca, Marina Guerrin, Michel Simon, Cécile Caubet, Emilie A. Leclerc, Guy SerreAbstract:Corneodesmosin (CDSN) was identified 20 years ago by raising monoclonal antibodies against human plantar stratum corneum. The protein is specific to corneodesmosomes, cell-junction structures that, in humans, are found in the epidermis, the hard palate epithelium, and the inner root sheath of the hair follicles. Synthesized by the granular keratinocytes and secreted via the lamellar bodies, CDSN is incorporated into the desmoglea of the desmosomes, shortly before their transformation into corneodesmosomes during cornification. CDSN displays adhesive properties, mostly attributable to its N-terminal glycine-rich domain, and is sequentially proteolyzed as corneocytes migrate towards the skin surface prior to desquamation. The recent inactivation of Cdsn in mice induced a lethal epidermal barrier disruption and hair follicle degeneration, related to corneodesmosome dysfunction. That confirmed the essential role of the protein in maintaining integrity of the epidermis and the hair follicle. The CDSN gene is located in PSORS1, the major psoriasis susceptibility locus on the chromosome 6, but to date its involvement in the disease pathophysiology is not clear. By contrast, two different monogenic diseases associated with nonsense mutations in CDSN, were recently identified. First, hypotrichosis simplex of the scalp in which mutated CDSN accumulates in the dermis and forms amyloid deposits; then, peeling skin disease in which the genetic defect induces dyscohesion of the stratum corneum, responsible for abnormal desquamation and increased skin penetration of allergens.
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Corneodesmosin structure function and involvement in pathophysiology
The Open Dermatology Journal, 2010Co-Authors: Nathalie Jonca, Marina Guerrin, Michel Simon, Cécile Caubet, Guy SerreAbstract:Corneodesmosin (CDSN) was identified in the early 90 th by raising monoclonal antibodies against human plantar stratum corneum. It is a protein specific to desmosomes that will undergo transformation into corneodesmosomes, i.e. in man, desmosomes of the epidermis, of the three epithelial layers of the inner root sheath of the hair follicles and of the hard palate epithelium. After its secretion by granular keratinocytes via the lamellar bodies, CDSN is incorporated into the desmoglea of the desmosomes shortly before their transformation into corneodesmosomes. CDSN displays adhesive properties, mostly attributable to its N-terminal glycine-rich domain, and is sequentially proteolyzed as corneocytes migrate towards the skin surface. The recent inactivation of Cdsn in mice induced a lethal epidermal barrier disruption and hair follicle degeneration related to desmosome dysfunction, confirming the essential role of the protein in epidermis and hair follicle integrity. CDSN is located on chromosome 6, in the major psoriasis susceptibility locus PSORS1. Intriguingly, the only monogenic disease identified so far associated with nonsense mutations in CDSN, leading to the formation of a truncated protein, is a rare autosomal dominant disease, hypotrichosis simplex of the scalp. In this review, we expose data from the discovery of the protein to the most recent findings related to the relationship between its structure and function. In particular, the important benefits of mouse models and human diseases for the comprehension of CDSN role in the epidermis and hair follicles are reported in details.
Akemi Ishida-yamamoto - One of the best experts on this subject based on the ideXlab platform.
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Clinical and molecular implications of structural changes to desmosomes and corneodesmosomes.
The Journal of dermatology, 2018Co-Authors: Akemi Ishida-yamamoto, Satomi Igawa, Mari Kishibe, Masaru HonmaAbstract:Desmosomes provide the main intercellular adhesive properties between epidermal keratinocytes. Their distribution becomes uneven in severe dermatitis, multiple allergies and metabolic wasting syndrome due to desmoglein 1 deficiency and the loss of intercellular adhesion or acantholysis. When keratinocytes differentiate from granular cells into cornified cells, desmosomes are transformed into corneodesmosomes and can provide stronger intercellular adhesion. Degradation of corneodesmosomes is a tightly regulated process involving a number of proteases and their inhibitors. Peripheral corneodesmosomes are protected from proteolytic degradation by the tight junction-related structures around them, and this construction provides the basis for the normal basket weave-like structure of the stratum corneum. In Netherton syndrome, which is caused by an absence of the protease inhibitor lymphoepithelial Kazal-type-related inhibitor, premature degradation of corneodesmosomes occurs due to the overactivation of proteases involved in corneodesmosome degradation. Inflammatory peeling skin disease is caused by the absence of Corneodesmosin, a unique component of corneodesmosomes. In this disease, corneodesmosomes are structurally abnormal, and their adhesiveness is compromised, which leads to intercellular splitting between the stratum corneum and stratum granulosum. The better we understand desmosome and corneodesmosome ultrastructure in normal and diseased skin, the clearer the physiological and pathological mechanisms of epidermal integrity become.
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Incomplete KLK7 Secretion and Upregulated LEKTI Expression Underlie Hyperkeratotic Stratum Corneum in Atopic Dermatitis
The Journal of investigative dermatology, 2016Co-Authors: Satomi Igawa, Mari Kishibe, Masako Minami-hori, Masaru Honma, Hisashi Tsujimura, Junko Ishikawa, Tsutomu Fujimura, Masamoto Murakami, Akemi Ishida-yamamotoAbstract:Atopic dermatitis (AD) is a common inflammatory skin disorder. Chronic AD lesions present hyperkeratosis, indicating a disturbed desquamation process. KLK7 is a serine protease involved in the proteolysis of extracellular corneodesmosome components, including desmocollin 1 and Corneodesmosin, which leads to desquamation. KLK7 is secreted by lamellar granules and upregulated in AD lesional skin. However, despite increased KLK7 protein levels, immunostaining and electron microscopy indicated numerous corneodesmosomes remaining in the uppermost layer of the stratum corneum from AD lesions. We aimed to clarify the discrepancy between KLK7 overexpression and retention of corneodesmosomes on AD corneocytes. Western blot analysis indicated abnormal Corneodesmosin degradation patterns in stratum corneum from AD lesions. The KLK activity of tape-stripped corneocytes from AD lesions was not significantly elevated in in situ zymography, which was our new attempt to detect the protease activity more precisely than conventional assays. This ineffective KLK activation was associated with impaired KLK7 secretion from lamellar granules and increased expression of LEKTI in AD. Such imbalances in protease-protease inhibitor interactions could lead to abnormal proteolysis of corneodesmosomes and compact hyperkeratosis. Upregulated expression of LEKTI might be a compensatory mechanism to prevent further barrier dysfunction in AD.
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The biology and regulation of corneodesmosomes
Cell and Tissue Research, 2015Co-Authors: Akemi Ishida-yamamoto, Satomi IgawaAbstract:The stratum corneum of the epidermis is composed of stacked dead corneocytes embedded in lipid layers and is the main protective shield of the skin. The thickness of the stratum corneum is maintained fairly constantly through the balance between new cell creation and old cell removal. Corneodesmosomes are the main intercellular adhesive structures in the stratum corneum. They are transformed from desmosomes at the most superficial layer of the stratum granulosum of the epidermis. The major compositional distinction from desmosomes is the presence of Corneodesmosin in the extracellular portion. Furthermore, corneodesmosomes are structurally different from desmosomes in that (1) they do not have a tri-lamellar desmoglea but rather one that is homogeneously electron-dense and (2) attachment plaques are integrated into a part of the cornified cell envelopes. When the extracellular regions of corneodesmosomes are fully degraded, desquamation occurs. The degradation process of corneodesmosomes is carefully controlled by a number of proteases and their inhibitors. The most important proteases involved in this process are the kallikrein-related peptidases. Their main inhibitor is the lympho-epithelial Kazal-type related inhibitor. Other regulators of this process include matriptase, meprin and mesotrypsin.
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Inflammatory peeling skin syndrome caused by homozygous genomic deletion in the PSORS1 region encompassing the CDSN gene.
Experimental dermatology, 2013Co-Authors: Akemi Ishida-yamamoto, Satomi Igawa, Masaru Honma, Masamoto Murakami, Laetitia Furio, Elodie Tron, Valérie Malan, Alain HovnanianAbstract:Peeling skin syndrome (PSS) type B is a rare recessive genodermatosis characterized by lifelong widespread, reddish peeling of the skin with pruritus. The disease is caused by small-scale mutations in the Corneodesmosin gene (CDSN) leading to premature termination codons. We report for the first time a Japanese case resulting from complete deletion of CDSN. Corneodesmosin was undetectable in the epidermis, and CDSN was unamplifiable by PCR. QMPSF analysis demonstrated deletion of CDSN exons inherited from each parent. Deletion mapping using microsatellite haplotyping, CGH array and PCR analysis established that the genomic deletion spanned 49-72 kb between HCG22 and TCF19, removing CDSN as well as five other genes within the psoriasis susceptibility region 1 (PSORS1) on 6p21.33. This observation widens the spectrum of molecular defects underlying PSS type B and shows that loss of these five genes from the PSORS1 region does not result in an additional cutaneous phenotype.
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Involvement of corneodesmosome degradation and lamellar granule transportation in the desquamation process
Medical Molecular Morphology, 2011Co-Authors: Akemi Ishida-yamamoto, Mari KishibeAbstract:Desquamation in the mammalian skin is a well-balanced process of producing corneocytes and shedding them from the surface of the skin. The corneodesmosome, which is a modified desmosome, is the main adhesive structure in the cornified cell layer. The major extracellular constituents of corneodesmosomes are desmoglein 1, desmocollin 1, and Corneodesmosin. Proteases involved in the degradation of corneodesmosomes and their inhibitors are secreted from lamellar granules in the granular cell layer. Genetic defects in Corneodesmosin and protease inhibitors result in accelerated desquamation and severe barrier impairment. Abnormalities in transportation and secretion of lamellar granules underlie ichthyosis seen in certain human diseases.
Marina Guerrin - One of the best experts on this subject based on the ideXlab platform.
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Expression of LRP1 in human epidermis.
2013Co-Authors: Marie-florence Galliano, Nathalie Jonca, Guy Serre, Eve Toulza, Steven L. Gonias, Marina GuerrinAbstract:Immunohistochemistry and immunofluorescence analyses on skin samples in the presence of 8G1 (A, B) or 5A6 mAbs (C–G). A, the α chain of LRP1 labeling shows weak cytoplasmic staining in the spinous layers while it appears to locate at the periphery in the upper layers of the epidermis. B, using immunofluorescence, the α chain of LRP1 labeling is detected in the granular layer of epidermis. The dermis was also labeled. C and D, the β chain of LRP1 is associated within the granular layer of epidermis. The dermis was positive. A, C, original magnification×200. B, D, bar, 15 µm. E–G, Double labeling for LRP1 and Corneodesmosin (E), involucrin (F) and desmocollin (G). LRP1 does not colocalize with Corneodesmosin or involucrin but colocalizes with desmocollin 1 within keratinocytes of the granular layer. D, E, F, nuclei were counterstained with TOTO. H, Biochemical analysis of LRP1 expression. The α chain and β chain of LRP1 were detected in RAW cells and in human epidermis by immunoprecipitation. Lysates from RAW cells or 300 µg of epidermal proteins (epid.) were incubated with 8G1 or 5A6 mAbs or without antibody (−). Standard immunoprecipitations were then applied. The blots were probed with the same antibodies. Under non-reducing conditions, the dimers formed by IgH and IgL chains were detected.
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Corneodesmosomes and Corneodesmosin: from the stratum corneum cohesion to the pathophysiology of genodermatoses.
European journal of dermatology : EJD, 2011Co-Authors: Nathalie Jonca, Marina Guerrin, Michel Simon, Cécile Caubet, Emilie A. Leclerc, Guy SerreAbstract:Corneodesmosin (CDSN) was identified 20 years ago by raising monoclonal antibodies against human plantar stratum corneum. The protein is specific to corneodesmosomes, cell-junction structures that, in humans, are found in the epidermis, the hard palate epithelium, and the inner root sheath of the hair follicles. Synthesized by the granular keratinocytes and secreted via the lamellar bodies, CDSN is incorporated into the desmoglea of the desmosomes, shortly before their transformation into corneodesmosomes during cornification. CDSN displays adhesive properties, mostly attributable to its N-terminal glycine-rich domain, and is sequentially proteolyzed as corneocytes migrate towards the skin surface prior to desquamation. The recent inactivation of Cdsn in mice induced a lethal epidermal barrier disruption and hair follicle degeneration, related to corneodesmosome dysfunction. That confirmed the essential role of the protein in maintaining integrity of the epidermis and the hair follicle. The CDSN gene is located in PSORS1, the major psoriasis susceptibility locus on the chromosome 6, but to date its involvement in the disease pathophysiology is not clear. By contrast, two different monogenic diseases associated with nonsense mutations in CDSN, were recently identified. First, hypotrichosis simplex of the scalp in which mutated CDSN accumulates in the dermis and forms amyloid deposits; then, peeling skin disease in which the genetic defect induces dyscohesion of the stratum corneum, responsible for abnormal desquamation and increased skin penetration of allergens.
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Corneodesmosin structure function and involvement in pathophysiology
The Open Dermatology Journal, 2010Co-Authors: Nathalie Jonca, Marina Guerrin, Michel Simon, Cécile Caubet, Guy SerreAbstract:Corneodesmosin (CDSN) was identified in the early 90 th by raising monoclonal antibodies against human plantar stratum corneum. It is a protein specific to desmosomes that will undergo transformation into corneodesmosomes, i.e. in man, desmosomes of the epidermis, of the three epithelial layers of the inner root sheath of the hair follicles and of the hard palate epithelium. After its secretion by granular keratinocytes via the lamellar bodies, CDSN is incorporated into the desmoglea of the desmosomes shortly before their transformation into corneodesmosomes. CDSN displays adhesive properties, mostly attributable to its N-terminal glycine-rich domain, and is sequentially proteolyzed as corneocytes migrate towards the skin surface. The recent inactivation of Cdsn in mice induced a lethal epidermal barrier disruption and hair follicle degeneration related to desmosome dysfunction, confirming the essential role of the protein in epidermis and hair follicle integrity. CDSN is located on chromosome 6, in the major psoriasis susceptibility locus PSORS1. Intriguingly, the only monogenic disease identified so far associated with nonsense mutations in CDSN, leading to the formation of a truncated protein, is a rare autosomal dominant disease, hypotrichosis simplex of the scalp. In this review, we expose data from the discovery of the protein to the most recent findings related to the relationship between its structure and function. In particular, the important benefits of mouse models and human diseases for the comprehension of CDSN role in the epidermis and hair follicles are reported in details.
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Corneodesmosin gene ablation induces lethal skin-barrier disruption and hair-follicle degeneration related to desmosome dysfunction.
Journal of Cell Science, 2009Co-Authors: Emilie A. Leclerc, Nathalie Jonca, Guy Serre, Anne Huchenq, Nicolas R. Mattiuzzo, Daniel Metzger, Pierre Chambon, Norbert B. Ghyselinck, Marina GuerrinAbstract:International audienceCorneodesmosin (CDSN) is specific to desmosomes of epithelia undergoing cornification, mainly the epidermis and the inner root sheath of the hair follicles. CDSN nonsense mutations are associated with hypotrichosis simplex of the scalp, a rare disease that leads to complete baldness in young adults. CDSN displays adhesive properties, mostly attributable to its N-terminal glycine-rich domain, and is sequentially proteolyzed as corneocytes migrate towards the skin surface. K14-promoter driven Cre-mediated deletion of Cdsn in mice resulted in neonatal death as a result of epidermal tearing upon minor mechanical stress. Ultrastructural analyses revealed a desmosomal break at the interface between the living and cornified layers. After grafting onto nude mice, knockout skin showed a chronic defect in the epidermal permeability barrier. The epidermis was first hyperproliferative with a thick cornified layer, then, both the epidermis and the hair follicles degenerated. In adults, Cdsn deletion resulted in similar histological abnormalities and in a lethal barrier defect. We demonstrate that Cdsn is not essential for skin-barrier formation in utero, but is vital throughout life to preserve this barrier by maintaining desmosome integrity. The strong adhesive function that the protein confers on corneodesmosomes also seems necessary for maintaining the architecture of the hair follicle
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Corneodesmosin gene ablation induces lethal skin-barrier disruption and hair-follicle degeneration related to desmosome dysfunction.
Journal of cell science, 2009Co-Authors: Emilie A. Leclerc, Nathalie Jonca, Guy Serre, Anne Huchenq, Nicolas R. Mattiuzzo, Daniel Metzger, Pierre Chambon, Norbert B. Ghyselinck, Marina GuerrinAbstract:Corneodesmosin (CDSN) is specific to desmosomes of epithelia undergoing cornification, mainly the epidermis and the inner root sheath of the hair follicles. CDSN nonsense mutations are associated with hypotrichosis simplex of the scalp, a rare disease that leads to complete baldness in young adults. CDSN displays adhesive properties, mostly attributable to its N-terminal glycine-rich domain, and is sequentially proteolyzed as corneocytes migrate towards the skin surface. K14-promoter driven Cre-mediated deletion of Cdsn in mice resulted in neonatal death as a result of epidermal tearing upon minor mechanical stress. Ultrastructural analyses revealed a desmosomal break at the interface between the living and cornified layers. After grafting onto nude mice, knockout skin showed a chronic defect in the epidermal permeability barrier. The epidermis was first hyperproliferative with a thick cornified layer, then, both the epidermis and the hair follicles degenerated. In adults, Cdsn deletion resulted in similar histological abnormalities and in a lethal barrier defect. We demonstrate that Cdsn is not essential for skin-barrier formation in utero, but is vital throughout life to preserve this barrier by maintaining desmosome integrity. The strong adhesive function that the protein confers on corneodesmosomes also seems necessary for maintaining the architecture of the hair follicle.