Disease relevance of Dsp

• Heterozygous DP-deficient mice exhibited excess adipocytes and fibrosis in the myocardium, increased myocyte apoptosis, cardiac dysfunction, and ventricular arrhythmias, thus recapitulating the phenotype of human ARVC [1].
• In this study, we characterized the ultrastructural localization of in vivo-bound IgG, Dsg3, and desmoplakin during the process of acantholysis in an active mouse PV model, using post-embedding immunoelectron microscopy [2].

High impact information on Dsp

• These differences were not dependent upon intercellular adhesion and were in marked contrast to keratinocytes conditionally null for another essential intercellular adhesion protein, desmoplakin (DP) [3].
• We further show that cardiac-restricted deletion of Dsp, encoding DP, impairs cardiac morphogenesis and leads to high embryonic lethality in the homozygous state [1].
• We established atrial myocyte cell lines expressing siRNA against desmoplakin (DP), responsible for human ARVC [1].
• The number of epidermal desmosomes in DP-null skin is similar to wild type (WT), but they lack keratin filaments, which compromise their function [4].
• In vitro, DP transgene expression rescues these defects [4].

Biological context of Dsp

• We have now rescued the extra-embryonic tissues by aggregation of tetraploid (wild-type) and diploid (Dsp mutant) morulae [5].
• In addition, the murine gene (Dsp) was mapped to mouse chromosome 13 by interspecific backcross mapping [6].
• We present evidence that Dsg2, which is located in desmoplakin-negative wild-type ES cells in non-desmosomal junctions, is needed for normal ES cell proliferation [7].
• This finding not only unveiled a new function for desmoplakin, but also provided the first opportunity to explore desmosome function during embryogenesis [8].
• This study therefore defines a new family of transcription factors, the DP proteins, members of which can interact combinatorially with E2F proteins to generate an array of DNA binding complexes that integrate cell-cycle progression with the transcription apparatus through the E2F binding site [9].

Anatomical context of Dsp

• Previously, we explored the functional importance of desmosomes by ablating the Dsp gene [5].
• Interestingly, although wild-type endothelial cells of capillaries do not form desmosomes, they possess unusual intercellular junctions composed of DP, PG and VE-cadherin [5].
• Rescuing desmoplakin function in extra-embryonic ectoderm reveals the importance of this protein in embryonic heart, neuroepithelium, skin and vasculature [5].
• Kaz was originally found in adult tissues, primarily epidermis, linking periplakin to the plasma membrane and colocalizing with desmoplakin in desmosomes [10].
• Instead, extended adherens junctions are formed in the heart, which contain desmosomal proteins, i.e., desmoplakin [11].

Associations of Dsp with chemical compounds

• A Triton treatment of the monolayer reveals that most of the desmoplakin present in either wild-type, keratin 8- or keratin 18-null hepatocytes is insoluble [12].
• Together, the data indicate that a proper alignment/deposition of desmoplakin with keratins and desmoglein in hepatocytes requires keratin 8, through a reciprocal phosphoserine-dependent process [12].
• We have shown that expression of the desmosomal protein desmoplakin decreases in the luminal uterine epithelium during the preimplantation period of pregnancy in mice [13].

Other interactions of Dsp

• An immunofluorescence examination revealed that oatp1 was co-located with desmoplakin, a marker for the basolateral (sinusoidal) membrane, and mrp2 was co-localized with CD26, a marker for the apical (canalicular) membrane, though they were both expressed throughout most of the cell membranes [14].
• Immunofluorescence analyses of these blastocysts showed, however, that the distribution of the desmosomal plaque protein desmoplakin was disturbed, whereas the adherens junction proteins E-cadherin and beta-catenin appeared to be unaffected [7].
• Genetically, loss-of-function mutations in desmosomal proteins (plakophilin, desmoplakin, or plakoglobin) have been associated with ARVC [15].
• Vimentin was still present in mesangial-like cells, but the proximal, distal, and collecting tubule cells contained uniform networks of cytokeratins K8-K18 and desmoplakin I and II around the cell peripheries [16].
• These results suggest that the C-terminus of DP plays a role in the attachment of IF to the desmosome and that a specific site is necessary for interaction with keratin IF [17].

Analytical, diagnostic and therapeutic context of Dsp

• By the time of implantation (between Days 4.5 and 5 of pregnancy), desmoplakin protein can barely be detected by SDS-PAGE and Western blotting, and by immunocytochemistry, it is restricted to well-spaced, punctate dots at the apicolateral junction [13].

References