-
International Review of Cell and... 2011Mammalian spermatogenesis, a complex process that involves the movement of developing germ cells across the seminiferous epithelium, entails extensive restructuring of... (Review)
Review
Mammalian spermatogenesis, a complex process that involves the movement of developing germ cells across the seminiferous epithelium, entails extensive restructuring of Sertoli-Sertoli and Sertoli-germ cell junctions. Presently, it is not entirely clear how zygotene spermatocytes gain entry into the adluminal compartment of the seminiferous epithelium, which is sealed off from the systemic circulation by the Sertoli cell component of the blood-testis barrier, without compromising barrier integrity. To begin to address this question, it is critical that we first have a good understanding of the biology and the regulation of different types of Sertoli-Sertoli and Sertoli-germ cell junctions in the testis. Supported by recent studies in the field, we discuss how crosstalk between different types of junctions contributes to their restructuring during germ cell movement across the blood-testis barrier. We place special emphasis on the emerging role of desmosome-like junctions as signal transducers during germ cell movement across the seminiferous epithelium.
Topics: Adherens Junctions; Animals; Desmosomes; Germ Cells; Humans; Intercellular Junctions; Male; Seminiferous Epithelium; Sertoli Cells; Signal Transduction
PubMed: 21199783
DOI: 10.1016/B978-0-12-385859-7.00005-7 -
Clinical and Experimental Immunology Jan 1997Epidermal blister formation is the hallmark of three cutaneous autoimmune diseases: pemphigus foliaceous (PF), pemphigus vulgaris (PV) and bullous pemphigoid (BP). In PF... (Review)
Review
Epidermal blister formation is the hallmark of three cutaneous autoimmune diseases: pemphigus foliaceous (PF), pemphigus vulgaris (PV) and bullous pemphigoid (BP). In PF and PV, blistering is due to acantholysis (cell-cell detachment) in the subcorneal and suprabasal epidermal layers, respectively, while BP is characterized by detachment of the basal epidermal cells from the underlying dermis. For several years, we have focused our research efforts on elucidating the pathogenic mechanisms operating in these bullous diseases. Early studies performed by our research group and others revealed that in all three diseases, the patients produce autoantibodies that bind to target antigens located on the surface of cells that are undergoing detachment. Thus it was hypothesized that these anti-epidermal autoantibodies played a role in initiating blister formation. We recognized that elucidating the normal mechanisms of epidermal cell-cell and cell-dermis adhesion would help us understand the abnormal epidermal cell detachment seen in these patients. We hypothesized that under normal conditions these adhesive mechanisms in the epidermis are complex and dynamic and mediated by the interaction of cell surface molecules unique to each layer of the epidermis. Also, we postulated that PV, PF and BP autoantibodies may cause cell detachment by impairing the function of their respective epidermal cell surfaces. Support for this hypothesis has come from recent studies which showed that PV and PF autoantibodies recognize distinct, yet related, desmosomal glycoproteins in the cadherin family of calcium-dependent adhesion molecules. The epidermal antigen in PV is desmoglein-3 (dsg3), while in PF it is desmoglein-1 (dsg1). These anti-epidermal autoantibodies have been shown to be pathogenic in passive transfer experiments. Neonatal mice injected with these antibodies develop intraepidermal blisters characteristic of the corresponding human disease. Autoantibodies in BP react with BP180 and BP230, two major components of the hemidesmosome, a cell structure involved in dermal-epidermal adhesion. Recent passive transfer mouse model studies performed in our laboratory have shown that anti-BP180 antibodies can induce subepidermal blistering in the experimental animals. Moreover, the pathogenic mechanism was shown to be dependent on complement activation and recruitment of neutrophils to the dermal-epidermal junction. In conclusion, desmosomal glycoproteins are the targets of autoimmune injury in PV and PF. The anti-epidermal autoantibodies may cause intraepidermal blisters by impairing the function of dsg1 and dsg3. In BP the hemidesmosome is the target. It appears that antiBP180 antibodies cause subepidermal blister formation by triggering a complement- and neutrophil-mediated inflammatory process.
Topics: Animals; Autoantibodies; Autoimmunity; Desmosomes; Humans; Mice; Pemphigoid, Bullous; Pemphigus; Skin
PubMed: 9020929
DOI: No ID Found -
The Journal of Biological Chemistry Jan 2011The aim of our study was to investigate the association of desmosomal proteins with cholesterol-enriched membrane domains, commonly called membrane rafts, and the...
The aim of our study was to investigate the association of desmosomal proteins with cholesterol-enriched membrane domains, commonly called membrane rafts, and the influence of cholesterol on desmosome assembly in epithelial Madin-Darby canine kidney cells (clone MDc-2). Biochemical analysis proved an association of desmosomal cadherin desmocollin 2 (Dsc2) in cholesterol-enriched fractions that contain membrane raft markers caveolin-1 and flotillin-1 and the novel raft marker ostreolysin. Cold detergent extraction of biotinylated plasma membranes revealed that ∼60% of Dsc2 associates with membrane rafts while the remainder is present in nonraft and cholesterol-poor membranes. The results of immunofluorescence microscopy confirmed colocalization of Dsc2 and ostreolysin. Partial depletion of cholesterol with methyl-β-cyclodextrin disturbs desmosome assembly, as revealed by sequential recordings of live cells. Moreover, cholesterol depletion significantly reduces the strength of cell-cell junctions and partially releases Dsc2 from membrane rafts. Our data indicate that a pool of Dsc2 is associated with membrane rafts, particularly with the ostreolysin type of membrane raft, and that intact membrane rafts are necessary for desmosome assembly. Taken together, these data suggest cholesterol as a potential regulator that promotes desmosome assembly.
Topics: Animals; Caveolin 1; Cell Adhesion; Cell Line; Cell Membrane; Cholesterol; Desmocollins; Desmosomes; Dogs; Fungal Proteins; Hemolysin Proteins; Kidney; Membrane Glycoproteins; Membrane Microdomains; Membrane Proteins
PubMed: 21071449
DOI: 10.1074/jbc.M110.189464 -
Current Biology : CB Jul 2001Three desmoglein isoforms collaborate with desmocollins to build the adhesive core of desmosomes. A recent study has shown that altering the ratio of desmoglein isoforms... (Review)
Review
Three desmoglein isoforms collaborate with desmocollins to build the adhesive core of desmosomes. A recent study has shown that altering the ratio of desmoglein isoforms influences epidermal barrier function, suggesting distinct roles for these cadherins that extend beyond adhesion.
Topics: Animals; Cadherins; Cell Adhesion; Cytoskeletal Proteins; Desmocollins; Desmogleins; Desmoplakins; Desmosomes; Epidermis; Humans; Protein Isoforms
PubMed: 11509257
DOI: 10.1016/s0960-9822(01)00346-3 -
Human Molecular Genetics Dec 2011Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inheritable myocardial disorder associated with fibrofatty replacement of myocardium and ventricular...
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inheritable myocardial disorder associated with fibrofatty replacement of myocardium and ventricular arrhythmia. A subset of ARVC is categorized as Naxos disease, which is characterized by ARVC and a cutaneous disorder. A homozygous loss-of-function mutation of the Plakoglobin (Jup) gene, which encodes a major component of the desmosome and the adherens junction, had been identified in Naxos patients, although the underlying mechanism remained elusive. We generated Jup mutant mice by ablating Jup in cardiomyocytes. Jup mutant mice largely recapitulated the clinical manifestation of human ARVC: ventricular dilation and aneurysm, cardiac fibrosis, cardiac dysfunction and spontaneous ventricular arrhythmias. Ultra-structural analyses revealed that desmosomes were absent in Jup mutant myocardia, whereas adherens junctions and gap junctions were preserved. We found that ventricular arrhythmias were associated with progressive cardiomyopathy and fibrosis in Jup mutant hearts. Massive cell death contributed to the cardiomyocyte dropout in Jup mutant hearts. Despite the increase of β-catenin at adherens junctions in Jup mutant cardiomyoicytes, the Wnt/β-catenin-mediated signaling was not altered. Transforming growth factor-beta-mediated signaling was found significantly elevated in Jup mutant cardiomyocytes at the early stage of cardiomyopathy, suggesting an important pathogenic pathway for Jup-related ARVC. These findings have provided further insights for the pathogenesis of ARVC and potential therapeutic interventions.
Topics: Animals; Arrhythmias, Cardiac; Arrhythmogenic Right Ventricular Dysplasia; Cell Death; Desmosomes; Fibrosis; Gene Deletion; Heart Conduction System; Humans; Mice; Mice, Mutant Strains; Myocardium; Myocytes, Cardiac; Organ Specificity; Sarcomeres; Wnt Signaling Pathway; gamma Catenin
PubMed: 21880664
DOI: 10.1093/hmg/ddr392 -
The Journal of Investigative Dermatology Jul 2003Recessive mutations in the desmosomal plaque protein plakophilin 1 (PkP1) underlie ectodermal dysplasia/skin fragility syndrome (MIM 604536). We undertook an...
Alterations in desmosome size and number coincide with the loss of keratinocyte cohesion in skin with homozygous and heterozygous defects in the desmosomal protein plakophilin 1.
Recessive mutations in the desmosomal plaque protein plakophilin 1 (PkP1) underlie ectodermal dysplasia/skin fragility syndrome (MIM 604536). We undertook an immunohistochemical and quantitative electron microscopic examination of suprabasal desmosomes from 4 skin samples from 3 PkP1 deficient patients, an unaffected carrier with a PKP1 heterozygous acceptor splice site mutation and 5 healthy control subjects. Desmosomal plaque size (>50 desmosomes per individual) and frequency (>20 high power fields, HPF) were assessed. Compared with controls, desmosomes were reduced dramatically both in size (49%) and frequency (61%) in the lower suprabasal layers (LSB) in PkP1 null patients (P<0.01). In the LSB compartment of the heterozygous carrier, corresponding reductions were 37% and 20%, respectively (P<0.01). Surprisingly, the PkP1 null patient's upper suprabasal layer, (USB), desmosome size was larger (59%, P<0.01) than the control value, and showed increased desmoglein 1 and PkP2 USB staining. The USB desmosome frequency in PKP1 null patients was similar to the LSB compartment (but reduced by 43% compared to USB controls). The carrier showed no difference in the USB desmosome size and frequency compared with the controls (P>0.05). The PKP1 null patients showed poorly developed inner and outer desmosomal plaques. Thus, both the patients and unaffected carrier showed reductions in the LSB desmosome size and number; despite only PkP1 null patients exhibiting any phenotype. These findings attest to the molecular recruiting and stabilizing roles of PkP1 in desmosome formation, particularly in the LSB compartment.
Topics: Adolescent; Adult; Antibodies, Monoclonal; Child, Preschool; Desmosomes; Epidermis; Female; Fluorescent Antibody Technique; Heterozygote; Homozygote; Humans; Keratinocytes; Male; Microscopy, Electron; Plakophilins; Proteins; Skin Diseases
PubMed: 12839569
DOI: 10.1046/j.1523-1747.2003.12324.x -
British Journal of Cancer Jun 2007Much evidence now attests to the importance of desmosomes and their constituents in cancer. Alterations in the expression of desmosomal components could contribute to... (Review)
Review
Much evidence now attests to the importance of desmosomes and their constituents in cancer. Alterations in the expression of desmosomal components could contribute to the progression of the disease by modifying intracellular signal transduction pathways and/or by causing reduced cell adhesion. The Wnt/beta-catenin pathway is a potential target because of the involvement of the cytoplasmic desmosomal protein plakoglobin. Loss of desmosomal adhesion is a prerequisite for the epithelial-mesenchymal transition, implicated in the conversion of early stage tumours to invasive cancers.
Topics: Cadherins; Cell Membrane; Desmosomes; Humans; Models, Biological; Mutation; Neoplasms; Signal Transduction; beta Catenin; gamma Catenin
PubMed: 17519903
DOI: 10.1038/sj.bjc.6603808 -
The Journal of Cell Biology May 1993
Review
Topics: Animals; Cadherins; Cytoskeletal Proteins; Desmoplakins; Desmosomes; Humans; Terminology as Topic
PubMed: 8486729
DOI: 10.1083/jcb.121.3.481 -
Cellular and Molecular Life Sciences :... Sep 2003Desmosomes represent major intercellular adhesive junctions at basolateral membranes of epithelial cells and in other tissues. They mediate direct cell-cell contacts and... (Review)
Review
Desmosomes represent major intercellular adhesive junctions at basolateral membranes of epithelial cells and in other tissues. They mediate direct cell-cell contacts and provide anchorage sites for intermediate filaments important for the maintenance of tissue architecture. There is increasing evidence now that desmosomes in addition to a simple structural function have new roles in tissue morphogenesis and differentiation. Transmembrane glycoproteins of the cadherin superfamily of Ca(2+)-dependent cell-cell adhesion molecules which mediate direct intercellular interactions in desmosomes appear to be of central importance in this respect. The complex network of proteins forming the desmosomal plaque associated with the cytoplasmic domain of the desmosomal cadherins, however, is also involved in junction assembly and regulation of adhesive strength. This review summarizes the structural features of these desmosomal proteins, their function during desmosome assembly and maintenance, and their role in development and disease.
Topics: Amino Acid Motifs; Animals; Cadherins; Cell Adhesion; Cell Differentiation; Cytoskeletal Proteins; Desmosomes; Humans; Intermediate Filament Proteins; Morphogenesis; Plectin; Skin Diseases
PubMed: 14523549
DOI: 10.1007/s00018-003-3050-7 -
The Journal of Investigative Dermatology Oct 2020Rosacea is a common chronic inflammation of sebaceous gland-rich facial skin characterized by severe skin dryness, elevated pH, transepidermal water loss, and decreased...
Rosacea is a common chronic inflammation of sebaceous gland-rich facial skin characterized by severe skin dryness, elevated pH, transepidermal water loss, and decreased hydration levels. Until now, there has been no thorough molecular analysis of permeability barrier alterations in the skin of patients with rosacea. Thus, we aimed to investigate the barrier alterations in papulopustular rosacea samples compared with healthy sebaceous gland-rich skin, using RNA sequencing analysis (n = 8). Pathway analyses by Cytoscape ClueGO revealed 15 significantly enriched pathways related to skin barrier formation. RT-PCR and immunohistochemistry were used to validate the pathway analyses. The results showed significant alterations in barrier components in papulopustular rosacea samples compared with sebaceous gland-rich skin, including the cornified envelope and intercellular lipid lamellae formation, desmosome and tight junction organizations, barrier alarmins, and antimicrobial peptides. Moreover, the barrier damage in papulopustular rosacea was unexpectedly similar to atopic dermatitis; this similarity was confirmed by immunofluorescent staining. In summary, besides the well-known dysregulation of immunological, vascular, and neurological functions, we demonstrated prominent permeability barrier alterations in papulopustular rosacea at the molecular level, which highlight the importance of barrier repair therapies for rosacea.
Topics: DNA-Binding Proteins; Desmosomes; Fluorescent Antibody Technique; Humans; Kallikreins; Permeability; Principal Component Analysis; RNA-Seq; Rosacea; Signal Transduction; Skin; Tight Junctions
PubMed: 32199994
DOI: 10.1016/j.jid.2020.02.025