desmosomal cell adhesion in mammalian development

ARTICLE IN PRESS

0171-9335/$ - se

doi:10.1016/j.ej

�CorrespondUSA. Tel.: +7

E-mail addr

European Journal of Cell Biology 84 (2005) 215–223

www.elsevier.de/ejcb

REVIEW

Desmosomal cell adhesion in mammalian development

Xing Chenga, Zhining Dena, Peter J. Kocha,b,�

aDepartment of Dermatology, Baylor College of Medicine, Houston, TX, USAbDepartment of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

Abstract

Defects in desmosome-mediated cell–cell adhesion can lead to tissue fragility syndromes. Both inherited andacquired diseases caused by desmosomal defects have been described. The two organs that appear most vulnerable tothese defects are the skin with its appendages, and the heart. Furthermore, the analysis of genetically engineered micehas led to the discovery that desmosomal proteins are also required for normal embryonic development. Knockoutmice for several desmosomal proteins die in utero. Depending on the protein studied, death occurs either around thetime of implantation, at mid-gestation or shortly before birth. So far, it appears that structural defects leading toabnormal histo-architecture and tissue fragility are the main cause of death, i.e. there is no evidence that loss of adesmosomal protein would abort specific cell lineages or differentiation programs. Nevertheless, we are only beginningto understand the functions of individual desmosomal proteins during development. This review focuses on the role ofdesmosomes during mouse embryonic development.r 2004 Elsevier GmbH. All rights reserved.

Keywords: Desmosomes; Embryogenesis; Cell adhesion; Cytoskeleton; Desmogleins; Desmocollins; Plakins; Armadillo proteins;

Mouse development

Contents

Occurrence, structure and molecular composition of desmosomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216

Desmosomes in mouse embryonic development. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217

Pre-implantation development. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217

Implantation and early post-implantation development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219

Mid-gestation to birth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220

Newborn and adult mice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220

Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221

e front matter r 2004 Elsevier GmbH. All rights reserved.

cb.2004.12.008

ing author. Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030,

13 798 3308; fax: +713798 3800.

ess: [email protected] (P.J. Koch).

www.elsevier.de/ejcb

ARTICLE IN PRESSX. Cheng et al. / European Journal of Cell Biology 84 (2005) 215–223216

Occurrence, structure and molecular

composition of desmosomes

Desmosomes are cell–cell adhesion structures (junc-tions) that are most abundant in tissues prone tomechanical stress, for example the epidermis and themyocardium (see references in Franke et al., 1982;Kartenbeck et al., 1983; Koch and Franke, 1994;Schwarz et al., 1990), and appear to assemble duringdevelopment when strong and stable intercellular adhe-sion is required. Nevertheless, desmosomes are also verydynamic structures that can be assembled and disas-sembled in response to signals from the micro-environ-ment. This dynamic process is necessary in order toallow for morphogenetic processes during pre- and post-natal development to occur, such as the formation ofectodermal appendages (e.g. hair follicles and mammary

Desmogl

Outer dense plaque

Innerdense plaque

A

E-cad

Dsc

Dsg

β-Cat

α-Cat

PG

PKPs

DP

IF

Actin

α-Actinin

Membran

Fig. 1. (A) Simplified model of the proteins and molecular int

desmosomes (right panel), respectively. Note that the scheme is not

such as E-cadherin (E-cad), as well as catenins (a-catenin, a-Cat; b-with desmosomal cadherins (desmocollins, Dsc; desmogleins, Dsg) a

desmoplakin (DP). Note that plakoglobin and p0071 (not shown, s

junctions anchor micro (actin) filaments, whereas desmosomes anc

desmosome from newborn mouse back skin.

glands; e.g. Nanba et al., 2000, 2001; Runswick et al.,2001).Ultra-structurally, desmosomes consist of the desmo-

glea, i.e. the extracellular core domain that oftencontains a mid-line between the plasma membranes ofadjacent cells, and the intracellular symmetrical elec-tron-dense plaques, each of which can be furthersubdivided into an outer and an inner dense plaque(Fig. 1). The outer dense plaques are attached to theinner surface of the plasma membrane and consist of theCOOH-terminal domains of the desmosomal transmem-brane adhesion molecules, primarily the desmogleins(dsg) and desmocollins (dsc), and plaque proteins suchas periplakin, envoplakin, plakoglobin (pg), p0071,plakophilins (pkp) and the NH2-terminus of desmopla-kin (dp) (e.g. (Getsios et al., 2004; North et al., 1999).The COOH-terminus of dp extends to the inner dense

ea

B

e

eractions that establish adherens junctions (left panel) and

drawn to scale. Adherens junctions contain classical cadherins,

catenin, b-Cat; plakoglobin, PG). Desmosomes are assemblednd the plaque proteins plakoglobin, plakophilins (PKPs), and

ee text) are components of both types of junctions. Adherens

hor intermediate filaments (IF). (B) Electron micrograph of a

ARTICLE IN PRESSX. Cheng et al. / European Journal of Cell Biology 84 (2005) 215–223 217

plaque, where it binds to keratin intermediate filaments.Plakoglobin (formerly also known as g-catenin) andp0071 are components of both adherens junctions anddesmosomes, and are in fact thought to be important incoordinating the assembly and function of these celladhesion organelles [e.g. (Bierkamp et al., 1999; Calkinset al., 2003; Isac et al., 1999; Setzer et al., 2004)].The desmosomal transmembrane core consists of

type-1 transmembrane glycoproteins that belong to thedesmoglein and desmocollin subfamily of cadherins(calcium-dependent cell adhesion receptors), respec-tively. Six desmogleins (dsg1a; dsg1b; dsg1g; dsg2,dsg3, dsg4) (Whittock (2003) refers to dsg1b and dsg1gas dsg5 and dsg6, respectively) and three desmocollins(dsc1-3) have been identified so far (Buxton et al., 1993;Garrod et al., 2002a; Kljuic et al., 2003; Kljuic andChristiano, 2003; Koch and Franke, 1994; Pulkkinen etal., 2003). Two of these proteins, dsg1b and dsg1g; areencoded by the mouse, but not the human genome.Desmocollins are particularly interesting due to the factthat each dsc gene encodes two proteins that differ onlywith respect to their COOH-terminal cytoplasmicdomains. In vitro studies suggest that the longer ‘‘a’’variant of dsc may be the more important isoform,because of its ability to bind desmosomal plaqueproteins [e.g. (Troyanovsky et al., 1994) and referencesin (Garrod et al., 2002a)]. The ‘‘b’’ variant does not bindcrucial desmosomal components such as plakoglobin. Infact, only the dsc3b COOH-terminus has been shown tobind a plaque protein, plakophilin 3 (Bonne et al., 2003).Nevertheless, it remains to be seen if a specific functioncan be assigned to the ‘‘b’’ forms in vivo (see also Chenget al., 2004).It is thought that heterophilic interactions between the

extracellular domains of the desmosomal transmem-brane components provide strong cell–cell adhesion(Chitaev and Troyanovsky, 1997; He et al., 2003). Thecytoplasmic domains of the transmembrane proteinsand the plaque proteins assemble the plaque which inturn connects the desmosome to the intermediatefilament cytoskeleton, thus providing a transcellularnetwork of structural proteins that provide mechanicalresilience to the tissue. Fig. 1 outlines basic molecularinteractions that establish desmosomes (for a moredetailed discussion of molecular interactions betweendesmosomal proteins see for example Garrod et al.,2002b; Getsios et al., 2004; Koeser et al., 2003).

Desmosomes in mouse embryonic development

Pre-implantation development

In the following paragraphs, we will summarizeresearch that highlights the role of cadherin-based

cell junctions, in particular desmosomes, in normalembryogenesis.The first cell adhesion system that is activated in the

mammalian embryo consists of E-cadherin and itsassociated catenin complex (b-catenin, a-catenin). Theseproteins are already present in the fertilized egg (Ohsugiet al., 1996). However, they remain largely inactive untilthe eight-cell stage. Consequently, the cells of the earlycleavage stage embryo are only loosely attached to eachother (Fig. 2). At the eight-cell stage, posttranslationalmodifications of E-cadherin and/or b-catenin arethought to activate the pre-existing cadherin–catenincomplex resulting in an asymmetrical distribution of thecadherin/catenin complex along the lateral cell–cellborders of blastomeres and the induction of strongcell–cell adhesion leading to ‘‘compaction’’ (Fig. 2). Thecritical role of the E-cadherin/catenin complex at thecompaction stage has been demonstrated in vitro and invivo. E-cadherin null embryos initially undergo compac-tion due to the presence of maternally derived E-cadherin. However, further development to the matureblastocyst stage is blocked and embryo implantationdoes not occur. Mutant embryos either ‘‘decompact’’,i.e. lose cell adhesion altogether, or form abnormalblastocysts (Ohsugi et al., 1997; Riethmacher et al.,1995). Similarly, a-catenin mutants show lethal celladhesion defects in pre-implantation embryos (Torres etal., 1997). Interestingly, b-catenin null embryos proceedthrough implantation and die around embryonic day 7(E7), due to gastrulation defects (Haegel et al., 1995;Huelsken et al., 2000; Morkel et al., 2003). b-Cateninnull embryos do not form mesoderm and headstructures. The studies described above suggest that asignaling rather than an adhesion defect causes thelethal phenotype. It is likely that other armadilloproteins, such as plakoglobin, can compensate for theloss of b-catenin in the early embryo. Interestingly, lossof plakoglobin prevents neither normal pre-implanta-tion development nor implantation (see also below).After compaction, the embryo develops into a

blastula. The blastula consists of two cell layers,trophectoderm (TE) and inner cells mass (ICM) (Fig.2). The ICM will later develop into the embryo proper,i.e. generate all embryonic tissues. Embryonic stem cells,which are used to generate knockout mice, are derivedfrom ICM cells. The TE is a polarized single-layeredepithelium that subsequently differentiates into severalextraembryonic tissues. The TE cells form apicaljunctional complexes consisting of tight junctions,adherens junctions, gap junctions and desmosomes.The latter junction type is connected to keratinintermediate filaments (IF) (Jackson et al., 1980).Morphological and biochemical studies indicate thatdesmosomes are first assembled at the late morula stage.However, ‘‘mature desmosomes’’, as judged by electronmicroscopy, appear to assemble first in the TE (Fleming

ARTICLE IN PRESS

A B

C D

G H

FE

I

J

ICM

BC

TE

ZP

Fig. 2. (A–H) Different stages of pre-implantation development of the mouse embryo: (A) Two-cell stage (ZP; zona pellucida), (B)

four-cell stage, (C) eight-cell stage, (D) compaction stage, (E, F) blastocyst stage (ICM, inner cell mass; BC, blastocoel; TE,

trophectoderm), (G) hatching blastocyst (arrow depicts area where the embryo is hatching through the zona pellucida), (H) hatched

blastocysts, (I) immunofluorescence micrograph of a blastocyst stained with anti-desmoplakin antibodies. Note the punctated

staining pattern. Each dot represents an individual desmosome. (J) Trophoblast cells (staining of trophoblast outgrowth culture; see

Jackson et al., 1980) assemble intermediate filaments, as demonstrated by the staining with an anti-keratin antibody (Troma I)

(Kemler et al., 1981).

X. Cheng et al. / European Journal of Cell Biology 84 (2005) 215–223218

et al., 2000; Jackson et al., 1980). The cell biologicalmechanisms that lead to desmosome assembly in theearly embryo are not well understood. Biochemicalstudies suggested that the transmembrane componentsdsc2 and dsg2 are expressed later in development thanthe plaque components plakoglobin and desmoplakin(Fleming et al., 1994). Therefore, it has been speculatedthat desmosome assembly is triggered by the availabilityof the desmosomal cadherins.Intuitively, it would appear that an intact desmo-

some/IF network is required to maintain the integrity ofthe late blastula-stage embryo. The TE surrounds theblastocoel, i.e. it has to withstand the pressure from thisfluid-filled cavity. Furthermore, during hatching (Fig.2), the process in which the embryo squeezes through ahole in the zona pellucida in preparation for implanta-tion into the uterus, the TE should be exposed tosignificant mechanical stress. Nevertheless, mouse mu-tants that lack either dsg2 or desmoplakin, both ofwhich are thought to be crucial for cell adhesion and IF

anchorage in the early embryo, develop into morpho-logically normal blastocysts that hatch in vitro. Desmo-plakin null embryos implant but die shortly thereafterdue to defects in extraembryonic tissues (see below).Dsg2�/� embryos also die around the time of implanta-tion, however, the exact time point and cause ofembryonic death have not yet been determined (Eshkindet al., 2002).The dsg2 null blastocysts also showed an abnormal

(cytoplasmic) distribution of desmoplakin in TE cells.Desmoplakin is required to link desmosomes to the IFcytoskeleton. Nevertheless, failure to anchor IF isunlikely to cause the peri-implantation lethal phenotype,since mouse mutants, that lack embryonic type 1keratins (K18/K19) and do not form a normal IFnetwork, proceed through implantation and die aroundmid-gestation (Hesse et al., 2000).Interestingly, defects were observed in mouse em-

bryonic stem cells that were homozygous for the dsg2null allele. ES cells do not form classical desmosomes,


suggesting that this cadherin has cellular functionsindependent of desmosomes.

Implantation and early post-implantation

development

Desmosomes are assembled in the epithelium thatlines the inner surface of the uterus (endometrium). Inpreparation for implantation, desmoplakin synthesis isdown-regulated in these cells, which might facilitatetrophoblast invasion of the endometrium and, conse-quently, embryo implantation (Illingworth et al., 2000).In response to implantation, fibroblastic stroma cells ofthe endometrium undergo a morphological and bio-chemical transformation, the ‘‘decidual reaction’’ or‘‘decidualization’’. During this process, the intercellularspace becomes progressively smaller while extensive cell-to-cell contacts and junctional complexes are beingdeveloped, i.e. the decidual cells show some character-istics of epithelial cells. Adhering junctions assembled inthis tissue have been described as ‘‘desmosome-like’’ (seereferences in Andrade et al., 1994). Nevertheless, adetailed analysis of the proteins present in these

Yolksac Cavity

Ectoplacental Ca

Exocoelomic Cav

Amniotic Cavity

Ectoplacental Co

Ectoderm

Mesoderm

Visceral Endoder

Decidua

Parietal Endoder

A

Fig. 3. (A) Immuno-histochemical staining with an anti-keratin antib

E6.5-E7 mouse embryo. Note the positive reaction in the endoderma

the lower portion of (A).

junctions is still forthcoming. Interestingly, desmoplakinis expressed in a punctate fashion in cells undergoingdecidualization, suggesting a junctional localization ofthis protein (Andrade et al., 1994; Illingworth et al.,2000).At E5, embryos have implanted and assemble

desmosomes in extra-embryonic tissues. From E6 on,desmosomes are abundant in the extra-embryonicectoderm, the visceral (proximal) endoderm and theectoplacental cone (example of E6.5-E7 embryo inFig. 3; (Gallicano et al., 1998; Jackson et al., 1981).Desmoplakin null embryos begin to show defectsbetween E5 and E6, and all mutants have died by E6.5(Gallicano et al., 1998). Dp�/� embryos have a reducednumber of desmosomes and lack proper desmosome-IFcoupling. As indicated above, lack of proper IFformation is unlikely to cause the lethal phenotype atthis stage, since mutants that lack IF die around E9.5due to fragility of extraembryonic tissues (cytolysis oftrophoblast giant cells; Hesse et al., 2000). The expres-sion of dsg2, dsc2 and plakophilin 2 was reduced indp�/� mutants, however, clustering of the trans-membrane proteins did still occur. Interestingly, the

vity

ity

ne

m

m

B

ody (TROMA 1) (Kemler et al., 1981) of a section through an

l layers and the ectoplacental cone. (B) Higher magnification of


expression or distribution of marker proteins foradherens junctions (e.g. E-cadherin) was not affectedby the dp null mutation up to E6.5 (Gallicano et al.,1998). Mutant embryos were fragile and showed defectsin the proper development of histo-architecture, e.g. theproamnion cavity was often poorly formed. Further-more, loss of cell-to-cell adhesion was observed betweenvisceral endoderm cells and, maybe secondary to theendoderm defect, in embryonic ectoderm (which doesnot assemble desmosomes at this stage; Gallicano et al.,1998; Jackson et al., 1981). Consequently, tracerpenetration assays revealed that the visceral endodermfailed to form a proper barrier around the embryonicectoderm, and it has been suggested that this mightcontribute to the early embryonic death of dp�/�

mutants (Gallicano et al., 2001).

Mid-gestation to birth

In order to examine the role of desmoplakin at laterstages of development, the Fuchs laboratory utilized atechnique called ‘‘tetraploid rescue’’ to generate dp�/�

embryos that proceed through implantation and theearly stages of organogenesis (Gallicano et al., 2001). Inthis technique, tetraploid wild type cells are aggregatedwith dp�/� cells to form chimeric embryos. Aftertransfer of these embryos to recipient mice, thetetraploid cells form extraembryonic tissues and allowthe embryo to proceed through implantation and earlypost-implantation development. The dp�/� cells developinto the embryo proper. Dp�/� embryos developed untilmid-gestation, when they showed defects in desmosome-rich tissues such as the neuro-epithelium, the heart andthe surface ectoderm (which will later form theepidermis). At E10, mutant embryos were extremelysmall and malformed. The histo-architecture of the headfolds and the neural canal as well as the heart wereaffected. The heart was beating very slowly. The defectsin heart and neuro-epithelium are reminiscent of thedefects observed in N-cadherin null mutants which alsodie around E10 (Radice et al., 1997). In these mice,cardiac differentiation proceeds normally, but theadhesive integrity of the myocardial epithelium is notmaintained, and the heart tube essentially disintegrates.Interestingly, dp�/� mutants also showed a reduction

in blood capillaries and defects in the endothelial cellslining the capillaries. Dp is a component of the‘‘complexus adhaerentes’’. These endothelial junctionscontain plakoglobin and classical cadherins (VE-cad-herin), however, they lack the desmosomal transmem-brane proteins (Kowalczyk et al., 1998; Schmelz et al.,1994; Schmelz and Franke, 1993).Two groups generated plakoglobin null mice (Bier-

kamp et al., 1996; Isac et al., 1999; Ruiz et al., 1996).These animals also develop a lethal heart phenotype due

to a rupture of ventricles and blood flooding thepericardium. Interestingly, the time frame during whichpg�/� embryos die is quite long, ranging from E10.5 toE17.5.Desmosomes and adherens junctions are present in

the intercalated discs of myocardiocytes (see referencesin Schwarz et al., 1990). It appears that neither type ofjunction is formed in pg�/� cells. Instead, these animalsdeveloped a new type of junction that containsdesmosomal proteins (e.g. dp) and adherens junctionproteins (e.g. b-catenin). Desmosomal transmembraneproteins were not clustered, but distributed diffuselyover the cell membrane.One of the groups that generated pg�/� mice obtained

animals that almost survived to term (Bierkamp et al.,1999). These mutants developed skin defects that weredescribed as subcorneal acantholysis, i.e. suprabasalcells losing cell-to-cell adhesion leading to blisterformation just below the stratum corneum (the deadlayer of corneocytes that covers the epidermis). Skindesmosomes were significantly reduced in their abun-dance and appeared morphologically altered, i.e. theylacked the outer plaques and were rarely attached to IF.Interestingly, co-immuno precipitation assays indicatedthat b-catenin interacts with dsg in pg�/� epidermalcells, suggesting that this protein might, at leastpartially, compensate for the loss of plakoglobin.Compensation by b-catenin and/or other armadilloproteins might also explain why pg�/� mice die laterthan dp�/� mice.The phenotypes described above are consistent with

the idea that pg is indispensable for the sorting ofadhesion molecules into different types of junctions,thereby establishing the morphological and biochemicalidentity of desmosomes and adherens junctions.Skin blistering was also observed in late embryos with

a tissue-specific dp�/� mutation in stratified epithelia(Vasioukhin et al., 2001). Loss of dp led to a detachmentof desmosomes and IF, resulting in fragility mainly ofthe basal and immediate suprabasal cell layers. Inter-estingly, a reduced number of adherens junctions wasobserved in these mouse mutants.

Newborn and adult mice

Several mouse lines with defects in newborn skin dueto mutations in desmosomal genes have been described,e.g. dsg3 (Koch et al., 1997, 1998), dsg4 (Kljuic et al.,2003), and dsc1 (Cheng et al., 2004; Chidgey et al., 2001)mutant mice. Furthermore, transgenic mice eitherexpressing wild-type or truncated versions of desmoso-mal transmembrane proteins (dsg3) (Allen et al., 1996;Elias et al., 2001; Merritt et al., 2002), or plaque proteins(Charpentier et al., 2000), have been generated. Thesemouse models have been reviewed recently (Cheng and


Koch, 2004), and will therefore not be discussed indetail. These animal experiments demonstrated thatdesmosomal proteins are required for the maintenanceof the skin and for the normal development andhomeostasis of skin appendages, such as hair follicles.This is further supported by the growing list of inheritedhuman skin and heart diseases that can be traced tomutations in desmosomal genes (dsg1, dsg4, dp, pg,plakophilin 1; see references in Cheng and Koch, 2004).

Conclusions

Cell adhesion organelles, such as desmosomes, areoften viewed as static structures that only providestructural reinforcement to allow tissues to withstandmechanical stress. Although this feature is clearlyimportant, there are other aspects of cell junctions thatneed to be considered. The cadherin-based junctionsdiscussed in this review function in cell type-specificcontact formation, mechanical reinforcement of celladhesion and cell signaling. The notion that thesejunctions can act as signaling centers is illustrated bythe fact that they contain dual-function adaptermolecules that act as structural proteins as well assignal transducers (b-catenin and plakoglobin can signalthrough the WNT pathway; e.g. Charpentier et al.,2000; Conacci-Sorrell et al., 2002; Hu et al., 2003;Barker and Clevers, 2000; Zhurinsky et al., 2000a,b).Furthermore, the assembly of junctional complexes ishighly regulated and allows for spatial-temporal controlof cell–cell adhesion, which is critical for cell sorting andthe development of the proper histo-architecture ofvarious tissues during embryonic development. Interest-ingly, there is cross-talk between adherens junctions anddesmosomes, which appears to be regulated by plako-globin and p0071 (see above and Calkins et al., 2003;Setzer et al., 2004).At least six desmogleins and three desmocollins are

synthesized in the mouse. A systematic evaluation oftheir expression during embryogenesis is still forth-coming. It will be interesting to see which dsc and dsgisoforms are expressed in early embryos and whetherthey exert different functions.

Acknowledgements

This work is dedicated to Werner W. Franke who hasbeen a wonderful teacher and mentor to P.J. Koch.Most of the work summarized here was built on hisbasic work in the field of desmosomal adhesionmolecules, and was dependent on the excellent researchtools that his laboratory has generated over the years, inparticular antibodies to various desmosomal compo-

nents. This work was supported in part by grantsAR47343 and AR50439 from the National Institutes ofHealth (NIH/NIAMS) awarded to P.J. Koch.

References

Allen, E., Yu, Q.C., Fuchs, E., 1996. Mice expressing a mutant

desmosomal cadherin exhibit abnormalities in desmosomes,

proliferation, and epidermal differentiation. J. Cell Biol.

133, 1367–1382.

Andrade, C.G., Savino, W., Abrahamsohn, P.A., Zorn, T.M.,

1994. Distribution of desmoplakin I/II in endometrial cells

of mice in the artificially induced decidua. Tissue Cell 26,

639–647.

Barker, N., Clevers, H., 2000. Catenins, Wnt signaling and

cancer. Bioessays 22, 961–965.

Bierkamp, C., Mclaughlin, K.J., Schwarz, H., Huber, O.,

Kemler, R., 1996. Embryonic heart and skin defects in mice

lacking plakoglobin. Dev. Biol. 180, 780–785.

Bierkamp, C., Schwarz, H., Huber, O., Kemler, R., 1999.

Desmosomal localization of beta-catenin in the skin of

plakoglobin null-mutant mice. Development 126, 371–381.

Bonne, S., Gilbert, B., Hatzfeld, M., Chen, X., Green, K.J.,

van Roy, F., 2003. Defining desmosomal plakophilin-3

interactions. J. Cell Biol. 161, 403–416.

Buxton, R.S., Cowin, P., Franke, W.W., Garrod, D.R., Green,

K.J., King, I.A., Koch, P.J., Magee, A.I., Rees, D.A.,

Stanley, J.R., 1993. Nomenclature of the desmosomal

cadherins. J. Cell Biol. 121, 481–483.

Calkins, C.C., Hoepner, B.L., Law, C.M., Novak, M.R.,

Setzer, S.V., Hatzfeld, M., Kowalczyk, A.P., 2003. The

armadillo family protein p0071 is a VE-cadherin- and

desmoplakin-binding protein. J. Biol. Chem. 278,

1774–1783.

Charpentier, E., Lavker, R.M., Acquista, E., Cowin, P., 2000.

Plakoglobin suppresses epithelial proliferation and hair

growth in vivo. J. Cell Biol. 149, 503–520.

Cheng, X., Koch, P.J., 2004. In vivo function of desmosomes.

J. Dermatol. 31, 171–187.

Cheng, X., Mihindukulasuriya, K., Den, Z., Kowalczyk, A.P.,

Calkins, C.C., Ishiko, A., Shimizu, A., Koch, P.J., 2004.

Assessment of splice variant-specific functions of desmo-

collin 1 in the skin. Mol. Cell Biol. 24, 154–163.

Chidgey, M., Brakebusch, C., Gustafsson, E., Cruchley, A.,

Hail, C., Kirk, S., Merritt, A., North, A., Tselepis, C.,

Hewitt, J., Byrne, C., Fassler, R., Garrod, D., 2001. Mice

lacking desmocollin 1 show epidermal fragility accompa-

nied by barrier defects and abnormal differentiation. J. Cell

Biol. 155, 821–832.

Chitaev, N.A., Troyanovsky, S.M., 1997. Direct Ca2+-

dependent heterophilic interaction between desmosomal

cadherins, desmoglein and desmocollin, contributes to

cell–cell adhesion. J. Cell Biol. 138, 193–201.

Conacci-Sorrell, M., Zhurinsky, J., Ben Ze’ev, A., 2002. The

cadherin–catenin adhesion system in signaling and cancer.

J. Clin. Invest. 109, 987–991.

Elias, P.M., Matsuyoshi, N., Wu, H., Lin, C., Wang, Z.H.,

Brown, B.E., Stanley, J.R., 2001. Desmoglein isoform


distribution affects stratum corneum structure and func-

tion. J. Cell Biol. 153, 243–249.

Eshkind, L., Tian, Q., Schmidt, A., Franke, W.W., Windoffer,

R., Leube, R.E., 2002. Loss of desmoglein 2 suggests

essential functions for early embryonic development and

proliferation of embryonal stem cells. Eur. J. Cell Biol. 81,

592–598.

Fleming, T.P., Butler, L., Lei, X., Collins, J., Javed, Q., Sheth,

B., Stoddart, N., Wild, A., Hay, M., 1994. Molecular

maturation of cell adhesion systems during mouse early

development. Histochemistry 101, 1–7.

Fleming, T.P., Ghassemifar, M.R., Sheth, B., 2000. Junctional

complexes in the early mammalian embryo. Semin. Reprod.

Med. 18, 185–193.

Franke, W.W., Moll, R., Schiller, D.L., Schmid, E., Karten-

beck, J., Mueller, H., 1982. Desmoplakins of epithelial and

myocardial desmosomes are immunologically and bio-

chemically related. Differentiation 23, 115–127.

Gallicano, G.I., Bauer, C., Fuchs, E., 2001. Rescuing

desmoplakin function in extra-embryonic ectoderm reveals

the importance of this protein in embryonic heart,

neuroepithelium, skin and vasculature. Development 128,

929–941.

Gallicano, G.I., Kouklis, P., Bauer, C., Yin, M., Vasioukhin,

V., Degenstein, L., Fuchs, E., 1998. Desmoplakin is

required early in development for assembly of desmosomes

and cytoskeletal linkage. J. Cell Biol. 143, 2009–2022.

Garrod, D.R., Merritt, A.J., Nie, Z., 2002a. Desmosomal

cadherins. Curr. Opin. Cell Biol. 14, 537–545.

Garrod, D.R., Merritt, A.J., Nie, Z., 2002b. Desmosomal

adhesion: structural basis, molecular mechanism and

regulation. Mol. Membr. Biol. 19, 81–94.

Getsios, S., Huen, A.C., Green, K.J., 2004. Working out the

strength and flexibility of desmosomes. Nat. Rev. Mol. Cell

Biol. 5, 271–281.

Haegel, H., Larue, L., Ohsugi, M., Fedorov, L., Herrenknecht,

K., Kemler, R., 1995. Lack of beta-catenin affects

mouse development at gastrulation. Development 121,

3529–3537.

He, W., Cowin, P., Stokes, D.L., 2003. Untangling desmoso-

mal knots with electron tomography. Science 302, 109–113.

Hesse, M., Franz, T., Tamai, Y., Taketo, M.M., Magin, T.M.,

2000. Targeted deletion of keratins 18 and 19 leads to

trophoblast fragility and early embryonic lethality. EMBO

J. 19, 5060–5070.

Hu, P., Berkowitz, P., O’Keefe, E.J., Rubenstein, D.S., 2003.

Keratinocyte adherens junctions initiate nuclear signaling

by translocation of plakoglobin from the membrane to the

nucleus. J. Invest. Dermatol. 121, 242–251.

Huelsken, J., Vogel, R., Brinkmann, V., Erdmann, B.,

Birchmeier, C., Birchmeier, W., 2000. Requirement for

beta-catenin in anterior–posterior axis formation in mice. J.

Cell Biol. 148, 567–578.

Illingworth, I.M., Kiszka, I., Bagley, S., Ireland, G.W.,

Garrod, D.R., Kimber, S.J., 2000. Desmosomes are

reduced in the mouse uterine luminal epithelium during

the preimplantation period of pregnancy: a mechanism for

facilitation of implantation. Biol. Reprod. 63, 1764–1773.

Isac, C.M., Ruiz, P., Pfitzmaier, B., Haase, H., Birchmeier, W.,

Morano, I., 1999. Plakoglobin is essential for myocardial

compliance but dispensable for myofibril insertion into

adherens junctions. J. Cell Biochem. 72, 8–15.

Jackson, B.W., Grund, C., Schmid, E., Burki, K., Franke,

W.W., Illmensee, K., 1980. Formation of cytoskeletal

elements during mouse embryogenesis. Intermediate fila-

ments of the cytokeratin type and desmosomes in

preimplantation embryos. Differentiation 17, 161–179.

Jackson, B.W., Grund, C., Winter, S., Franke, W.W.,

Illmensee, K., 1981. Formation of cytoskeletal elements

during mouse embryogenesis. II. Epithelial differentiation

and intermediate-sized filaments in early postimplantation

embryos. Differentiation 20, 203–216.

Kartenbeck, J., Franke, W.W., Moser, J.G., Stoffels, U., 1983.

Specific attachment of desmin filaments to desmosomal

plaques in cardiac myocytes. EMBO J. 2, 735–742.

Kemler, R., Brulet, P., Schnebelen, M.T., Gaillard, J., Jacob,

F., 1981. Reactivity of monoclonal antibodies against

intermediate filament proteins during embryonic develop-

ment. J. Embryol. Exp. Morphol. 64, 45–60.

Kljuic, A., Bazzi, H., Sundberg, J.P., Martinez-Mir, A.,

O’Shaughnessy, R., Mahoney, M.G., Levy, M., Montagu-

telli, X., Ahmad, W., Aita, V.M., Gordon, D., Uitto, J.,

Whiting, D., Ott, J., Fischer, S., Gilliam, T.C., Jahoda,

C.A., Morris, R.J., Panteleyev, A.A., Nguyen, V.T.,

Christiano, A.M., 2003. Desmoglein 4 in hair follicle

differentiation and epidermal adhesion: evidence from

inherited hypotrichosis and acquired pemphigus vulgaris.

Cell 113, 249–260.

Kljuic, A., Christiano, A.M., 2003. A novel mouse desmoso-

mal cadherin family member, desmoglein 1 gamma. Exp.

Dermatol. 12, 20–29.

Koch, P.J., Franke, W.W., 1994. Desmosomal cadherins:

another growing multigene family of adhesion molecules.

Curr. Opin. Cell Biol. 6, 682–687.

Koch, P.J., Mahoney, M.G., Cotsarelis, G., Rothenberger, K.,

Lavker, R.M., Stanley, J.R., 1998. Desmoglein 3 anchors

telogen hair in the follicle. J. Cell Sci. 111, 2529–2537.

Koch, P.J., Mahoney, M.G., Ishikawa, H., Pulkkinen, L.,

Uitto, J., Shultz, L., Murphy, G.F., Whitaker-Menezes, D.,

Stanley, J.R., 1997. Targeted disruption of the pemphigus

vulgaris antigen (desmoglein 3) gene in mice causes loss of

keratinocyte cell adhesion with a phenotype similar to

pemphigus vulgaris. J. Cell Biol. 137, 1091–1102.

Koeser, J., Troyanovsky, S.M., Grund, C., Franke, W.W.,

2003. De novo formation of desmosomes in cultured cells

upon transfection of genes encoding specific desmosomal

components. Exp. Cell Res. 285, 114–130.

Kowalczyk, A.P., Navarro, P., Dejana, E., Bornslaeger, E.A.,

Green, K.J., Kopp, D.S., Borgwardt, J.E., 1998. VE-

cadherin and desmoplakin are assembled into dermal

microvascular endothelial intercellular junctions: a pivotal

role for plakoglobin in the recruitment of desmoplakin to

intercellular junctions. J. Cell Sci. 111, 3045–3057.

Merritt, A.J., Berika, M.Y., Zhai, W., Kirk, S.E., Ji, B.,

Hardman, M.J., Garrod, D.R., 2002. Suprabasal desmo-

glein 3 expression in the epidermis of transgenic mice results

in hyperproliferation and abnormal differentiation. Mol.

Cell Biol. 22, 5846–5858.

Morkel, M., Huelsken, J., Wakamiya, M., Ding, J., van de

Wetering, M., Clevers, H., Taketo, M.M., Behringer, R.R.,


Shen, M.M., Birchmeier, W., 2003. Beta-catenin regulates

Cripto- and Wnt3-dependent gene expression programs in

mouse axis and mesoderm formation. Development 130,

6283–6294.

Nanba, D., Hieda, Y., Nakanishi, Y., 2000. Remodeling of

desmosomal and hemidesmosomal adhesion systems during

early morphogenesis of mouse pelage hair follicles. J.

Invest. Dermatol. 114, 171–177.

Nanba, D., Nakanishi, Y., Hieda, Y., 2001. Changes in adhesive

properties of epithelial cells during early morphogenesis of

the mammary gland. Dev. Growth Differ. 43, 535–544.

North, A.J., Bardsley, W.G., Hyam, J., Bornslaeger, E.A.,

Cordingley, H.C., Trinnaman, B., Hatzfeld, M., Green,

K.J., Magee, A.I., Garrod, D.R., 1999. Molecular map of

the desmosomal plaque. J. Cell Sci. 112, 4325–4336.

Ohsugi, M., Hwang, S.Y., Butz, S., Knowles, B.B., Solter, D.,

Kemler, R., 1996. Expression and cell membrane localiza-

tion of catenins during mouse preimplantation develop-

ment. Dev. Dyn. 206, 391–402.

Ohsugi, M., Larue, L., Schwarz, H., Kemler, R., 1997. Cell-

junctional and cytoskeletal organization in mouse blasto-

cysts lacking E-cadherin. Dev. Biol. 185, 261–271.

Pulkkinen, L., Choi, Y.W., Kljuic, A., Uitto, J., Mahoney,

M.G., 2003. Novel member of the mouse desmoglein gene

family: Dsg1-beta. Exp. Dermatol. 12, 11–19.

Radice, G.L., Rayburn, H., Matsunami, H., Knudsen, K.A.,

Takeichi, M., Hynes, R.O., 1997. Developmental defects in

mouse embryos lacking N-cadherin. Dev. Biol. 181, 64–78.

Riethmacher, D., Brinkmann, V., Birchmeier, C., 1995. A

targeted mutation in the mouse E-cadherin gene results in

defective preimplantation development. Proc. Natl. Acad.

Sci. USA 92, 855–859.

Ruiz, P., Brinkmann, V., Ledermann, B., Behrend, M., Grund,

C., Thalhammer, C., Vogel, F., Birchmeier, C., Gunthert, U.,

Franke, W.W., Birchmeier, W., 1996. Targeted mutation of

plakoglobin in mice reveals essential functions of desmo-

somes in the embryonic heart. J. Cell Biol. 135, 215–225.

Runswick, S.K., O’Hare, M.J., Jones, L., Streuli, C.H.,

Garrod, D.R., 2001. Desmosomal adhesion regulates

epithelial morphogenesis and cell positioning. Nat. Cell

Biol. 3, 823–830.

Schmelz, M., Franke, W.W., 1993. Complexus adhaerentes, a

new group of desmoplakin-containing junctions in en-

dothelial cells: the syndesmos connecting retothelial cells of

lymph nodes. Eur. J. Cell Biol. 61, 274–289.

Schmelz, M., Moll, R., Kuhn, C., Franke, W.W., 1994.

Complexus adhaerentes, a new group of desmoplakin-

containing junctions in endothelial cells: II. Different types

of lymphatic vessels. Differentiation 57, 97–117.

Schwarz, M.A., Owaribe, K., Kartenbeck, J., Franke, W.W.,

1990. Desmosomes and hemidesmosomes: constitutive

molecular components. Annu. Rev. Cell Biol. 6, 461–491.

Setzer, S.V., Calkins, C.C., Garner, J., Summers, S., Green,

K.J., Kowalczyk, A.P., 2004. Comparative analysis of

armadillo family proteins in the regulation of A431

epithelial cell junction assembly, adhesion and migration.

J. Invest. Dermatol. 123, 426–433.

Torres, M., Stoykova, A., Huber, O., Chowdhury, K.,

Bonaldo, P., Mansouri, A., Butz, S., Kemler, R., Gruss,

P., 1997. An alpha-E-catenin gene trap mutation defines its

function in preimplantation development. Proc. Natl.

Acad. Sci. USA 94, 901–906.

Troyanovsky, S.M., Troyanovsky, R.B., Eshkind, L.G.,

Leube, R.E., Franke, W.W., 1994. Identification of amino

acid sequence motifs in desmocollin, a desmosomal

glycoprotein, that are required for plakoglobin binding

and plaque formation. Proc. Natl. Acad. Sci. USA 91,

10,790–10,794.

Vasioukhin, V., Bowers, E., Bauer, C., Degenstein, L., Fuchs,

E., 2001. Desmoplakin is essential in epidermal sheet

formation. Nat. Cell Biol. 3, 1076–1085.

Whittock, N.V., 2003. Genomic sequence analysis of the

mouse desmoglein cluster reveals evidence for six distinct

genes: characterization of mouse DSG4, DSG5, and DSG6.

J. Invest. Dermatol. 120, 970–980.

Zhurinsky, J., Shtutman, M., Ben Ze’ev, A., 2000a. Differ-

ential mechanisms of LEF/TCF family dependent tran-

scriptional activation by beta-catenin and plakoglobin.

Mol. Cell Biol. 20, 4238–4252.

Zhurinsky, J., Shtutman, M., Ben Ze’ev, A., 2000b. Plakoglo-

bin and beta-catenin: protein interactions, regulation and

biological roles. J. Cell Sci. 113, 3127–3139.

desmosomal cell adhesion in mammalian development

Documents