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Published on: January 12, 2015
Subcellular localization of desmosomal components is different between desmoglein3 knockout mice and pemphigus
Hitoshi Saito1, Atsushi Shimizu, Kazuyuki Tsunoda
1Department of Dermatology, Saitama Municipal Hospital, 2460 Mimuro, Midori-ku, Saitama-shi, Saitama 336-8522, Japan.
Background:
The desmoglein 3 (Dsg3) knockout mouse and pemphigus vulgaris (PV) mouse model present a similar type of supra-basal acantholysis, even though the subcellular mechanism is considered to be completely different.
Objectives:
To detect changes in the desmosomal molecular composition in Dsg3-/- mice and PV model mice to highlight the precise mechanism for acantholysis at an ultrastructural level.
Methods:
Using epithelia from Dsg3-/- mice, PV model mice, and their respective control mice, the desmosomal components were immunostained using a post-embedding immunogold labeling method, and their precise localization and the labeling density were statistically analyzed in the desmosomes before the occurrence of acantholysis.
Results:
Positive findings were detected in desmoplakin and plakoglobin. In the Dsg3-/- mice, the localization of desmoplakin shifted 12.6nm toward the cytoplasm and the plakoglobin labeling density per desmosome decreased 31% in the desmosomes. In the PV model mice Desmoplakin shifted 22.7nm more distantly from the plasma membrane but the labeling density per desmosome showed no significant difference, including plakoglobin. Similar results were obtained when analyzing the desmosomes of spinous cells in the mid-epidermis.
Conclusion:
These results showed the functional blocking of Dsg3 by autoantibody binding and the genetic defect of Dsg3 to induce different changes in the cytoplasmic desmosomal plaque proteins. A decrease in the level of plakoglobin is therefore not involved in the acantholysis in the PV model mice. The desmoplakin shift from the desmosomal plaque, which is induced by autoantibody binding under in vivo conditions in the PV model mouse, could be an early molecular change before the occurrence of acantholysis.
Insights
Genetic defects and autoantibodies targeting desmoglein 3 (Dsg3) cause distinct molecular changes in desmosomes. Plakoglobin levels do not decrease in pemphigus vulgaris (PV) mouse models, suggesting desmoplakin shifts precede acantholysis.
Area of Science:
- Dermatology
- Cell Biology
- Molecular Biology
Background:
- Pemphigus vulgaris (PV) and Dsg3 knockout mice exhibit similar supra-basal acantholysis.
- Subcellular mechanisms underlying acantholysis in these models were previously considered distinct.
Purpose of the Study:
- To investigate ultrastructural changes in desmosomal molecular composition.
- To elucidate the precise mechanism of acantholysis in Dsg3 knockout and PV mouse models.
Main Methods:
- Immunogold labeling of desmosomal components in epithelia from Dsg3-/- mice, PV model mice, and controls.
- Statistical analysis of desmosome localization and labeling density prior to acantholysis.
Main Results:
- Desmoplakin and plakoglobin localization/density were analyzed.
- In Dsg3-/- mice, desmoplakin shifted cytoplasmically, and plakoglobin density decreased.
- In PV mice, desmoplakin shifted away from the plasma membrane, with no significant change in plakoglobin density.
Conclusions:
- Genetic Dsg3 defects and PV autoantibodies induce differential changes in desmosomal plaque proteins.
- Reduced plakoglobin is not implicated in PV-induced acantholysis.
- Desmoplakin displacement in PV mice may be an early event preceding acantholysis.
