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Correspondence to Walter Birchmeier: wbirch{at}mdc-berlin.de
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Abstract |
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M. Behrend's present address is Franz Volhard Clinic, D-13125 Berlin, Germany.
Abbreviations used in this paper: ES, embryonic stem; IF, intermediate-sized filament; wt, wild-type.
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Introduction |
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Two types of "classical" cellcell junctions are found in vertebrates, adherens junctions and desmosomes, which have one plaque protein in common, plakoglobin (Cowin et al., 1986). In adherens junctions that comprise morphologically diverse forms such as puncta adhaerentia, fasciae adhaerentes, and zonulae adhaerentes, ß-catenin links cadherins to -catenin, thus mediating interaction with the actin cytoskeleton (Boller et al., 1985; Nagafuchi and Takeichi, 1989; Ozawa et al., 1989; Hülsken et al., 1994; Aberle et al., 1996). Typical desmosomes (maculae adhaerentes), which are characterized by the plaque protein desmoplakin (Franke et al., 1982), are found in epithelial cells, cardiomyocytes, meningothelial cells, and dendritic reticulum cells of lymph node follicles, where they anchor bundles of intermediate-sized filaments (IFs) of the cytokeratin, the desmin, or the vimentin type, respectively (Kartenbeck et al., 1983, 1984; Franke and Moll, 1987; Kuruc and Franke, 1988; van der Loop et al., 1995). In addition, desmoplakin has also been identified in the complexus adhaerens, an adhering junction characteristic of some endothelia, where it is essential for vascular development, as demonstrated by gene ablation in mice (Schmelz and Franke, 1993; Schmelz et al., 1994; Valiron et al., 1996; Kowalczyk et al., 1998; Gallicano et al., 2001; Zhou et al., 2004).
The plakophilin subfamily of arm repeat proteins comprises three members, plakophilins 13 (Kapprell et al., 1988; Hatzfeld et al., 1994, 2000; Heid et al., 1994; Schmidt et al., 1994, 1997, 1999; Mertens et al., 1996, 1999; Bonné et al., 1999). The arm protein p0071, occasionally also called plakophilin 4, is more closely related to another armadillo subfamily comprising proteins p120ctn, ARVCF, and neurojungin (Schmidt et al., 1999). Plakophilins 13 are juxtamembranous constituents of plaques of desmosomes and certain related junctions where they are tightly associated with other arm proteins, cadherins and desmoplakin, and are involved in the anchorage of IFs (Hatzfeld and Nachtsheim, 1996; Mertens et al., 1996, 1999; Schmidt et al., 1997, 1999; Bonné et al., 1999; Kowalczyk et al., 1999; North et al., 1999; Hatzfeld et al., 2000; Bornslaeger et al., 2001; Chen et al., 2002; Koeser et al., 2003). Plakophilins are also detected in the nucleus; for example, plakophilin 2 has been found in association with nucleoplasmic RNA polymerase III complexes (Mertens et al., 1996, 2001; Schmidt et al., 1997, 1999; Bonné et al., 1999). Although the function of ß-catenin in the nucleus is well known (Behrens et al., 1996; Eastman and Grosschedl, 1999; Hecht et al., 1999; Bienz and Clevers, 2000), similar roles for plakophilins have not yet been established. Plakophilin 2 occurs in all proliferative epithelial tissues and tumors as well as in the cardiomyocytes and Purkinje fiber cells of the heart (Mertens et al., 1996, 1999).
Striking similarities exist between the phenotypes generated by human and mouse mutations of desmosomal proteins (Ruiz et al., 1996; Bierkamp et al., 1996; Gallicano et al., 1998, 2001; Armstrong et al., 1999; McKoy et al., 2000; Norgett et al., 2000; Vasioukhin et al., 2001; Rampazzo et al., 2002; Alcalai et al., 2003). No mutations for plakophilin 2, which is the only plakophilin gene expressed in the heart, had been reported. Here, we describe the phenotype of plakophilin 2deficient mouse embryos, showing distortions of heart morphogenesis and stability, followed by cardiac rupture, blood leakage, and embryonic death. The analysis of the molecular organization of the affected tissue has allowed us to propose a molecular mechanism for these alterations as well as a general role of plakophilin 2 in junctional plaque organization.
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Results |
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Discussion |
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The analysis of the molecular changes in the cytoskeletal architecture of the plakophilin 2 mutant hearts has, however, revealed striking differences to ablations of plakoglobin and N-cadherin: while in plakoglobin-deficient embryonic hearts desmoplakin remains firmly associated with the plaques of the adhering junctions (Ruiz et al., 1996), this protein is no longer associated with the junctions in the absence of plakophilin 2. Rather, in the plakophilin 2deficient embryonic hearts desmoplakin is dispersed over the cytoplasm, where it frequently forms sizable aggregates located between the myofibril and IF arrays, away from the intercalated disks. We conclude therefrom that it is plakophilin 2, possibly together with plakoglobin, which is essential for fixing desmoplakin to the junctional plaques of cardiomyocytes. Our work also shows that both plakophilin 2 and desmoplakin are not required for the anchorage of myofibrils to adhering junctions of cardiomyocytes (see Fig. 5, a and b), as this has also been shown for plakoglobin (Isac et al., 1999). By contrast, the IF arrays normally interspersed between the myofibrils and enriched at the intercalated disks (e.g., Kartenbeck et al., 1983; Milner et al., 1996) are often displaced in the mutant, but still display associations with desmoplakin, including formations of swirls around the desmoplakin aggregates. These associations between IFs and desmoplakin away from the plasma membrane reflect the intimate binding of these proteins, compatible with results in cultured epithelial cells (Stappenbeck and Green, 1992; Stappenbeck et al., 1993; Kouklis et al., 1994; Bornslaeger et al., 1996, 2001; Smith and Fuchs, 1998; Kowalczyk et al., 1999; Vasioukhin et al., 2001; Chen et al., 2002). Our immunolocalization and biochemical data also demonstrate that in the plakophilin 2deficient mouse embryos, several proteins of the armadillo family such as ß-catenin, p120ctn, and also part of plakoglobin remain at the adhering junctions of the cardiac intercalated disks, despite the absence of plakophilin 2 and desmoplakin. This indicates that their binding to other plaque components, including the cytoplasmic portion of N-cadherin, is sufficient to secure their junctional integration. Plakophilin 2 binding, as reported from cell transfection and yeast two-hybrid experiments (Chen et al., 2002), is therefore not needed for association of ß-catenin, p120ctn, and part of plakoglobin with the cardiac junctions. However, the desmosomal cadherins (e.g., Dsg2) were largely absent from desmosomal junctions and were detergent extractable from mutant hearts. This higher detergent solubility of Dsg2 may be due to its exclusion from the cardiac junctions, similar to the detergent-extractable forms of nascent desmoglein from cultured cells (e.g., Pasdar and Nelson, 1989; Pasdar et al., 1991). Thus, our observations are compatible with reports on cultured cells that plakophilin 2 is a stabilizing binding partner of desmosomal cadherins (Chen et al., 2002; Koeser et al., 2003; see also Chitaev et al., 1996).
In contrast to the myocard, several epithelia show normal-looking desmosomes in the plakophilin 2deficient mutant embryos. These epithelia are known to contain plakophilin 3 (Bonné et al., 1998, 1999; Schmidt et al., 1999), which might structurally and functionally compensate for the absence of plakophilin 2. Whether plakophilin 1 can also compensate for plakophilin 2 in certain suprabasal epithelial cells (for in vitro experiments see Kowalczyk et al., 1999; Hofmann et al., 2000) remains to be examined. We have not been able to examine the functional roles of plakophilin 2 in epithelial differentiation and function, as the plakophilin 2 / embryos die early.
Hereditary human cardiomyopathies are characterized by impaired myocardial contractility and ventricular dilatation, and frequently also affect myofibril function. Mutations in genes coding for components of the contractile apparatus have been identified in cardiomyopathy (Thierfelder et al., 1994). Mutation of titin, a large cytoskeletal and signaling protein of cardiac muscles, can result in dilated cardiomyopathy with congestive heart failure (Gerull et al., 2002). After our report that ablation of the plakoglobin gene in mice leads to heart rupture (Ruiz et al., 1996), it has been found that Naxos disease is caused by deletion of plakoglobin that results in cardiomyopathy and skin defects (McKoy et al., 2000; Protonotarios et al., 2001; Narin et al., 2003). Mutations of desmoplakin and other junctional proteins in humans were recently also found to be associated with complex heart and skin disorders (Armstrong et al., 1999; Norgett et al., 2000; Alcalai et al., 2003; for reviews see Chidgey, 2002; Cheng and Koch, 2004). Therefore, it is tempting to speculate that other alterations of the plakophilin 2 gene than the null mutation reported here, or other types of interferences with plakophilin 2 function, might impair heart function and play a role in human heart disease.
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Materials and methods |
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Histology and immunohistochemistry
Embryos and yolk sacs were fixed in PBS containing 4% formaldehyde freshly prepared from paraformaldehyde, washed, embedded in paraffin, and sections were stained with hematoxylin and eosin. Transverse Epon sections of wt and plakophilin 2deficient embryos were stained with toluidine blue. For whole-mount immunohistochemistry, embryos were fixed in methanol/DMSO and incubated with primary anti PECAM-1 antibody (mAb; BD Biosciences), followed by incubation with secondary POD-conjugated donkey antirat antibody (Dianova) in 2% dissolved milk powder. DAB was used for color detection.
Immunofluorescence microscopy
Cryostat sections of wt and homozygous plakophilin 2 mutant mouse embryos at E10.75 were fixed with acetone at 20°C for 10 min, and were incubated with guinea pig or mouse mAbs to plakophilin 2 (Mertens et al., 1996, 2001; Borrmann, 2000), antibodies to desmoplakin (mAb "DP mix" from Progen Biotechnik GmbH, or polyclonal rabbit antibodies from NaTuTec), murine mAbs, guinea pig or rabbit antibodies to desmoglein Dsg2 (Progen; Schmelz et al., 1986; Nuber et al., 1996; Schäfer et al., 1996; Kurzen et al., 1998), ß-catenin (mAb; Zymed Laboratories), N-cadherin (mAb; Transduction Laboratories), or plakoglobin (mAb; Progen). Murine mAbs and guinea pig antibodies specific for cardiac -actin, desmin and vimentin (all from Progen), or for plakophilin 2 (Mertens et al., 1996, 1999) were applied. Fixed sections were exposed to primary antibodies for 30 min, followed by three washes with PBS and incubation with secondary antibodies coupled to Alexa 568 or Alexa 488 (MoBiTec) for 30 min. Samples were rinsed with PBS and mounted with Fluoromount (Biozol). Fluorescence micrographs were taken with Axiophot and LSM 510 microscopes (both from Carl Zeiss MicroImaging, Inc.).
Electron and immunoelectron microscopy
Embryos were dissected and fixed in 8% formaldehyde/0.1% glutaraldehyde in HEPES, osmicated, and embedded in Epon (Poly/Bed 812; Polysciences) using standard procedures. For immunoelectron microscopy, 5-µm-thick cryostat sections were mounted on coverslips, fixed for 10 min with 2% formaldehyde in PBS, permeabilized with 0.1% saponin in PBS for 5 min, and incubated for 1 h with the primary antibodies. After three washes with PBS, specimens were incubated with secondary, Nanogold-conjugated antibodies (BioTrend) for 24 h. Further treatment, including silver enhancement of the gold particles, was as described previously (Langbein et al., 2002). Samples were dehydrated and flat-embedded in Epon. Ultrathin sections were examined with an electron microscope (model EM 910; Carl Zeiss MicroImaging, Inc.).
Detergent extraction, gel electrophoreses, and Western blots
For Triton X-100 extraction, embryonic hearts were snap-frozen in liquid nitrogen and genotyped. Hearts were pooled, sonicated in lysis buffer (20 mM Hepes, pH 7.4, 150 mM NaCl, 0.5 mM CaCl2, and 1% Triton X-100), and centrifuged at 20,000 g for 15 min. Protein concentration was measured, and equal amounts of the Triton X-100 insoluble and soluble fractions were subjected to SDS-PAGE and transferred to nitrocellulose, and blots were probed several antibodies (see above) including -tubulin (Sigma-Aldrich) and pan-Erk (Cell Signaling, New England Biolabs, Inc.). For Western blotting, embryonic tissues were sonicated in ice-cold PBS and were boiled in SDS-containing loading buffer for 10 min at 95°C, and the homogenate was centrifuged. Equal amounts of total protein were subjected to SDS-PAGE, and blots were probed with the antibodies described above.
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Acknowledgments |
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This research was supported by a KAP fellowship of the MDC to M. Behrend and a fellowship of the Deutsche Forschungsgemeinschaft (Graduiertenkolleg) to K.S. Grossmann.
Submitted: 18 February 2004
Accepted: 25 August 2004
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