Desmoplakin is required early in development for assembly of desmosomes and cytoskeletal linkage

Desmosomes first assemble in the E3.5 mouse trophectoderm, concomitant with establishment of epithelial polarity and appearance of a blastocoel cavity . Throughout development, they increase in size and number and are especial ly abundant in epidermis and heart muscle. Desmosomes mediate cell-cell adh esion through desmosomal cadherins, which differ from classical cadherins i n their attachments to intermediate filaments (IFs), rather than actin fila ments. Of the proteins implicated in making this IF connection, only desmop lakin (DP) is both exclusive to and ubiquitous among desmosomes. To explore its function and importance to tissue integrity, we ablated the desmoplaki n gene. Homozygous -/- mutant embryos proceeded through implantation, but d id not survive beyond E6.5. Mutant embryos proceeded through implantation, but did not survive beyond E6.5. Surprisingly, analysis of these embryos re vealed a critical role for desmoplakin not only in anchoring Ifs to desmoso mes, but also in desmosome assembly and/or stabilization. This finding not only unveiled a new function for desmoplakin, but also provided the first o pportunity to explore desmosome function during embryogenesis. While a blas tocoel cavity formed and epithelial cell polarity was at least partially es tablished in the DP (-/-) embryos, the paucity of desmosomal cell-cell junc tions severely affected the modeling of tissue architecture and shaping of the early embryo.