Rescuing desmoplakin function in extra-embryonic ectoderm reveals the importance of this protein in embryonic heart, neuroepithelium, skin and vasculature.
Desmosomes mediate intercellular adhesion through desmosomal cadherins, which interface with plakoglobin (PG) and desmoplakin (DP) to associate with the intermediate filament (IF) cytoskeleton. Desmosomes first assemble in the E3.5 mouse trophectoderm, concomitant with establishment of epithelial polarity and appearance of a blastocoel cavity. Increasing in size and number, desmosomes continue their prominence in extra-embryonic tissues, but as development proceeds, they also become abundant in a number of embryonic tissues, including heart muscle, epidermis and neuroepithelium. Previously, we explored the functional importance of desmosomes by ablating the Dsp gene. Homozygous Dsp mutant embryos progressed through implantation, but did not survive beyond E6.5, owing to a loss or instability of desmosomes and tissue integrity. We have now rescued the extra-embryonic tissues by aggregation of tetraploid (wild-type) and diploid (Dsp mutant) morulae. These animals survive several days longer, but die shortly after gastrulation, with major defects in the heart muscle, neuroepithelium and skin epithelium, all of which possess desmosomes, as well as the microvasculature, which does not. Interestingly, although wild-type endothelial cells of capillaries do not form desmosomes, they possess unusual intercellular junctions composed of DP, PG and VE-cadherin. The severity in phenotype and the breadth of defects in the Dsp mutant embryo is greater than PG mutant embryos, substantiating redundancy between PG and other armadillo proteins (e.g. beta-catenin). The timing of lethality is similar to that of the VE-cadherin null embryo, suggesting that a participating cause of death may be a defect in vasculature, not reported for PG null embryos.
Gallicano
G I
GI
Howard Hughes Medical Institute, Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, IL 60637, USA.
Bauer
C
C
Fuchs
E
E
D000818:Animals; D001808:Blood Vessels / Q000196:embryology*; D016764:Cell Polarity; D003433:Crosses, Genetic; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051180:Desmoplakins; D003896:Desmosomes / Q000502:physiology*; D004475:Ectoderm / Q000166:cytology / Q000502:physiology*; D010064:Embryo Implantation; D005314:Embryonic and Fetal Development / Q000235:genetics / Q000502:physiology; D004848:Epithelium / Q000196:embryology; D005260:Female; D005313:Fetal Death; D006321:Heart / Q000196:embryology*; D006735:Horseradish Peroxidase / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009420:Nervous System / Q000196:embryology*; D011247:Pregnancy; D012867:Skin / Q000196:embryology*; D014327:Trophoblasts / Q000166:cytology / Q000502:physiology; D014781:Viscera / Q000196:embryology; D051185:gamma Catenin
D003598:Cytoskeletal Proteins; D051180:Desmoplakins; C495295:Dsp protein, mouse; D051185:gamma Catenin; D006735:Horseradish Peroxidase