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, whi ch interface with plakoglobin (PG) and desmoplakin (DP) to associate with t he intermediate filament (IF) cytoskeleton, Desmosomes first assemble in th e E3.5 mouse trophectoderm, concomitant with establishment of epithelial po larity and appearance of a blastocoel cavity, Increasing in size and number , desmosomes continue their prominence in extra-embryonic tissues, but as d evelopment proceeds, they also become abundant in a number of embryonic tis sues, 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 tiss ue integrity, We have now rescued the extraembryonic 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 w hich possess desmosomes, as well as the microvasculature, which does not, I nterestingly, although wild-type endothelial cells of capillaries do not fo rm desmosomes, they possess unusual intercellular junctions composed of DP, PG and VE-cadherin. The severity in phenotype and the breadth of defects i n the Dsp mutant embryo is greater than PG mutant embryos, substantiating r edundancy between PG and other armadillo proteins (e,g, beta -catenin), The timing of lethality is similar to that of the VE-cadherin null embryo, sug gesting that a participating cause of death may be a defect in vasculature, not reported for PG null embryos.