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

Abstract

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.

Desmosomes and Intermediate Filaments: Their Consequences for Tissue Mechanics

“…Although b-catenin, the homologue of PG in AJs, localized to desmosomes and could substitute for PG in cadherin clustering, it failed to recruit normal levels of PKP1 and DSP to the plaque (Bierkamp et al 1999;Acehan et al 2008). DSP KO embryos did not survive beyond embryonic day 6.5 and displayed severe defects in tissue architecture, shaping of the embryo, and in anchoring keratin filaments to desmosomes (Gallicano et al 1998). In an epidermisspecific DSP KO, intercellular separations were observed as expected (Vasioukhin et al 2001).…”

“…Desmosomes have been recognized early on as important sites for KIF formation and organization in vivo (Jackson et al 1980;Bologna et al 1986;Schwarz et al 2015), and genetic deletion of DSP can cause extensive reorganization or collapse of KIF, depending on the cell type (Gallicano et al 1998;Vasioukhin et al 2001;Sumigray and Lechler 2012). Moreover, DSP and DSG1 mutations can give rise to SPPK (OMIM #612908, #148700, respectively), a hyperkeratotic skin condition with fewer or smaller desmosomes in the suprabasal epidermis and perinuclear accumulation of KIF in DSP-associated SPPK (Wan et al 2004).…”

Ftm is a novel basal body protein of cilia involved in Shh signalling

“…1A). These comprise three coiled-coil domains, which are possibly involved in homopolymer formation (Zhao et al, 2003), one C2 domain, which is proposed to play a role in the binding of intermediate filament proteins (Gallicano et al, 1998), and a socalled RID domain. This domain was characterized in the Ftmrelated protein RPGRIP1 (retinitis pigmentosa GTPase regulator interacting protein 1) (Boylan and Wright, 2000;Hong et al, 2001).…”

Dynamics and unexpected localization of the plakin binding protein, kazrin, in mouse eggs and early embryos

“…Adherens junctions arise during embryogenesis at the 8-to 16-cell stage during compaction. Desmosome formation follows shortly thereafter (Ducibella et al, 1975;Jackson et al, 1980;Fleming et al, 1991;Gallicano et al, 1998). It is tempting to propose that kaz/actin binding at preimplantation stages may be a prerequisite for guiding actin to newly forming adherens junction.…”