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© The Rockefeller University Press, 0021-9525/1998//2009 $5.00
The Journal of Cell Biology, Volume 143, Number 7, , 1998 2009-2022

Desmoplakin Is Required Early in Development for Assembly of Desmosomes and Cytoskeletal Linkage

Howard Hughes Medical Institute and Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago Illinois 60637

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 especially abundant in epidermis and heart muscle. Desmosomes mediate cell–cell adhesion through desmosomal cadherins, which differ from classical cadherins in their attachments to intermediate filaments (IFs), rather than actin filaments. Of the proteins implicated in making this IF connection, only desmoplakin (DP) is both exclusive to and ubiquitous among desmosomes. To explore its function and importance to tissue integrity, we ablated the desmoplakin gene. Homozygous –/– mutant embryos proceeded through implantation, but did not survive beyond E6.5. Mutant embryos proceeded through implantation, but did not survive beyond E6.5. Surprisingly, analysis of these embryos revealed a critical role for desmoplakin not only in anchoring IFs to desmosomes, but also in desmosome assembly and/or stabilization. This finding not only unveiled a new function for desmoplakin, but also provided the first opportunity to explore desmosome function during embryogenesis. While a blastocoel cavity formed and epithelial cell polarity was at least partially established in the DP (–/–) embryos, the paucity of desmosomal cell–cell junctions severely affected the modeling of tissue architecture and shaping of the early embryo.

Key Words: desmoplakin • desmosomes • cadherins • embryonic lethal • knockout

Abbreviations used in this paper: aa, amino acids; BV, blood vessels; DAPI, 4, 6-diamidino-2-phenylindole; Dec, maternal decidua; DP, desmoplakin; Dsc, desmocollin; Dsg, desmoglein; Ect, primitive ectoderm; En, embryonic endoderm; EPC, ectoplacental cone; ES, embryonic stem; IF, intermediate filaments; PN, parietal endoderm; PN primitive endoderm, wt, wild-type; YS, yolk sac.

Drs. Gallicano and Kouklis contributed equally to this manuscript.

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