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* Kehua Li,1, Young Ryoo,1, Clair McGee,1 Akemi Ishida-Yamamoto,2 Jouni Uitto,1 and John F. Klement1
Department of Dermatology and Cutaneous Biology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania,1 Department of Dermatology, Asahikawa Medical College, Asahikawa 078-8510, Japan2
Received 5 February 2004/ Accepted 9 April 2004
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ABSTRACT |
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INTRODUCTION |
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Plectin, a versatile cytoskeletal linker protein, has an important role in maintaining the structural integrity of diverse cells and tissues, and it has been detected in desmosomal, hemidesmosomal, and perinuclear localizations in epidermal keratinocytes (7, 45, 55). Plectin deficiency in mice causes a blistering skin phenotype, abnormalities in skeletal muscle, and disintegration of intercalated disks in the heart, resulting in neonatal death at the age of 2 to 3 days (8). Hemidesmosomes have been found to be significantly reduced in number in plectin-deficient mice, indicating the role of plectin in the stability of hemidesmosomes. Human autosomal recessive disorder epidermolysis bullosa with muscular dystrophy results from defective or absent plectin due to the mutations in the plectin gene (PLEC1) (52).
BPAG1 was characterized as a major target for autoantibodies in the autoimmune blistering disease, bullous pemphigoid (38), but no human mutations have been identified as yet. The epithelial isoform of this protein is the intracellular component of hemidesmosomes, while the neuronal isoform functions as an essential cytoskeletal linker protein connecting actin microfilaments to intermediate filaments (57). Gene targeting of BPAG1 in mice results in hemidesmosomes which lack the inner plate and have no cytoskeleton attached (19). Mice also develop severe dystonia and sensory nerve degeneration due to the lack of the neural isoform binding and stabilizing microtubules (11, 56).
While plectin decorates intermediate filament (IF) networks and is a component of hemidesmosomes in stratified epithelia, desmoplakin connects IF to desmosomes. Desmoplakin, an integral component of inner desmosomal plague in a wide variety of tissues and cells, is essential for embryonic development (54). Mouse embryos deficient in desmoplakin proceed through implantation but do not survive beyond E6.5 due to major defects in the heart muscle and neuroepithelium (17, 18). In humans, a recessive mutation affecting desmoplakin tail and disrupting desmoplakin-IF interactions is not embryonic lethal but causes dilated cardiomyopathy, woolly hair, and keratoderma (40).
Envoplakin and periplakin, together with involucrin, were first characterized as precursors of the cornified cell envelope (CE) (44). Before the final assembly of the CE, envoplakin and periplakin have been detected in a soluble cytoplasmic pool, although these proteins mainly localize to desmosomes and interdesmosomal plasma membrane (47). No genetic disease has been found in humans due to the mutations in the genes encoding involucrin, envoplakin, or periplakin. However, all five plakin proteins, but most consistently envoplakin and periplakin, are recognized by circulating autoantibodies in patients with the autoimmune disease paraneoplastic pemphigus (9, 10, 35).
Although loricrin is a major protein of the epidermal CE, loricrin-deficient mice develop normally after a short delay in epithelial barrier development (28). As a surprise, involucrin knockout mice did not show any discernible phenotype (13), and the generation of envoplakin knockout mice revealed that this protein also is dispensable for normal viability (34).
The CE has been thought to play a crucial role in the epidermal barrier function, since it provides a rigid but flexible support to terminally differentiated keratinocytes in the cornified cell layer (23). Loricrin, involucrin, and envoplakin, as well as periplakin, become cross-linked to ceramides, the constituents of lipid layers, which provide the water barrier for the epidermis (36). Mice deficient for the sphingolipid activator proteins have revealed the importance of the extracellular lipid membranes for normal epidermal barrier formation and function (14). Transglutaminase 1 (TGase 1)-dependent cross-linking of proteins and lipids (39) is indispensable for normal epidermal development (27). TGase 1 is one of the genes implicated in autosomal recessive congenital ichthyosis in humans. Skin from TGase 1–/– mice, which die as neonates, lacks the normal insoluble cornified envelope and has impaired barrier function (30). At least 20 proteins become assembled into the CEs, and accordingly, it has been speculated that the cornified envelope assembly is guaranteed through compensatory mechanisms and the redundancy of its components (46).
Here, we report the generation of mice deficient in periplakin. Surprisingly, periplakin deficiency did not result in a discernible phenotype.
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MATERIALS AND METHODS |
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Generation of knockout mouse. The NotI-linearized targeting vector (25 µg) was electroporated into the mouse embryonic stem (ES) cells (5 x 107 cells) cultured under standard conditions (29). Clones were selected with G418 (250 µg/ml) and with 1 µM ganciclovir (Sigma, St. Louis, Mo.). This strategy selects those cells which have undergone homologous recombination events by simultaneously selecting for a neo gene and against a herpes simplex virus thymidine kinase gene placed at the end of the targeting vector (51). The selected ES clones were screened by PCR and Southern blotting for correct homologous recombination.
ES cells were microinjected into blastocysts obtained from C57BL/6J mice (Jackson Laboratories, Bar Harbor, Maine) and transferred to pseudopregnant B6CBA F1 mice (Jackson Laboratories). The chimeric animals were mated with wild-type C57BL/6J mice to determine the germ line transmission of the targeted Ppl allele. Heterozygotes were crossbred to produce Ppl–/– homozygous animals. The use of mice was approved by the Institutional Animal Care and Use Committee of Thomas Jefferson University.
Genotyping of the ES cells and mice. Both the ES cell clones and the animals were genotyped by using Southern blotting and/or PCR. For this purpose DNA from cells or mouse tissues was extracted by using standard protocols. Southern blotting was performed with genomic DNA digested with SacI restriction endonuclease and using a [32P]dCTP-labeled 1.3-kb PCR product as a probe. Primers for the amplification of the probe were 5'CTA TAA TTC CAA GTC ATC CAA GG-3' (forward) and 5'-GCC ATA AAG TTC CCT ATC ACT-3' (reverse). This probe recognizes a 7.5-kb SacI-fragment from the wild-type mouse DNA and a 4-kb SacI-fragment from the targeted allele.
In addition to Southern blotting, PCR was applied for genotyping of littermates. For this purpose, three primers were designed for the amplification of the mutant, wild type, or both alleles in the same reaction. Mouse periplakin exon 16-specific forward primer 5'-CTC ATA CGA GAA CAG GCT G-3' and exon 17-specific reverse primer 5'-CTG CTT GGC CAC CTG TAG-3' produce a 982-bp PCR product from the wild-type allele, while the exon 16-specific forward primer together with a PGK promoter-specific reverse primer, 5'-CCA GAG GCC ACT TGT GTA G-3', produce a 602-bp PCR product from the targeted allele.
Western analysis. A piece of newborn mouse dorsal skin was mixed with 150 µl of urea buffer (50 mM Tris-HCl [pH 7.4], 8 M urea, 1% Triton X-100), sonicated on ice, and cleared through centrifugation for 15 min at 10,000 x g in a microcentrifuge. An aliquot of the supernatant was mixed with an equal volume of Laemmli sample buffer (Bio-Rad) supplemented with ß-ercaptoethanol. For Western analysis, proteins were separated either by sodium dodecyl sulfate (SDS)-5% polyacrylamide gel electrophoresis or by 4 to 20% gradient polyacrylamide gel electrophoresis and transferred onto polyvinylidene difluoride membranes (Perkin-Elmer Life Sciences). The membranes were blocked for 1 h at room temperature (RT) with 1% bovine serum albumin (BSA) and 5% nonfat dried milk in phosphate-buffered saline (PBS). After the primary antibody incubation in 1% BSA in PBS overnight at 8°C, the membranes were washed four times, for 10 min each wash, in 0.5% Tween 20 in Tris-buffered saline, followed by incubations for 1 h at RT with the secondary antibody, and then washed again. The signal was developed using Western Lightning Chemiluminescence Reagent Plus (Perkin-Elmer Life Sciences).
Preparation of cornified envelopes. Pieces of newborn mouse dorsal skin (5 mm by 5 mm) were heated to 100°C for 20 min in CE isolation buffer containing 20 mM Tris-HCl (pH 7.5), 5 mM EDTA, 10 mM dithiotreitol, and 2% SDS. Cornified envelopes were pelleted by a 10-min centrifugation at 6,000 x g, washed in CE isolation buffer with 0.2% SDS, repelleted, and resuspended in the washing buffer. Envelopes were examined in a hemacytometer under phase microscopy.
Electron microscopy. Samples of neonatal mouse skin were fixed in half-strength Karnovsky fixative, and after secondary fixation in 1% osmium tetroxide, they were dehydrated in ethanol, stained en bloc using 1% uranyl acetate in 50% ethanol, and embedded in Epon resin (TAAB, Aldermaton, Berks, United Kingdom). Ultra-thin sections were stained with 1.5% uranyl acetate in methanol and with Reynold's lead citrate.
Dye exclusion assay. Periplakin heterozygous breeder mice were used to produce embryos to analyze skin water barrier formation by the dye exclusion assay. Embryos were harvested from pregnant females at the embryonic stages indicated in Fig. 5, the tail was removed for genotyping, and the dye exclusion assay was performed as described previously (20, 28, 34), using 0.0125% toluidine blue O (Fisher Scientific Corp, Pittsburgh, Pa.).
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Antibodies. A hybridoma culture supernatant containing mouse monoclonal antibody against the C-terminal region of the periplakin rod domain (PPL-488), recognizing an epitope within periplakin amino acids (aa) 1548 to 1583, was used in 1:10 dilution (1, 25). Affinity-purified rabbit polyclonal antienvoplakin antibody was a kind gift from L. Marekov and A. Kalinin and has been previously described (47). The following commercially available primary antibodies were used: goat antiplectin antibody against the C terminus of plectin (1:500; clone C20; Santa Cruz Biotechnology); rabbit antidesmoplakin antibody against the C-terminal nucleotides 4247 to 5228 (1:10,000; Serotech Ltd., Raleigh, N.C.); anti-involucrin monoclonal antibody (MAb) (1:2,000; NeoMarkers); antiactin MAb (1:10,000; Boehringer/Roche). Secondary antibodies were purchased from Jackson Laboratories. The horseradish peroxidase-conjugated anti-mouse, anti-goat, and anti-rabbit antibodies, as appropriate, were diluted 1:25,000 for the Western blotting. Species-specific secondary antibodies, conjugated with Texas Red and fluorescein isothiocyanate, were also purchased from Jackson Laboratories and used for indirect immunofluorescence in 1:500 dilution in PBS-1% BSA.
Nucleotide sequence accession numbers. Mouse periplakin gene sequences determined in this study were deposited in GenBank under accession numbers AF116519 to AF116523.
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RESULTS |
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Gene targeting of periplakin locus. To generate periplakin knockout mice, we constructed a targeting vector from a 4.5-kb lambda clone insert, encoding exons 13 to 16, serving as a 5' arm (Fig. 1A). To avoid the possibility of disturbing the ubinuclein gene, an internal fragment from periplakin exon 22 was used as the 3' arm. The homologous recombination of the targeting construct results in deletion of an 8-kb XhoI-XbaI fragment, removing periplakin exons 17 to 21 and a part of exon 22, replacing those sequences with a 1.9-kb neo gene under the control of PGK1 promoter (Fig. 1A). Out of 112 clones obtained through the positive-negative selection protocol, Southern blotting revealed that 5 were correctly targeted. All five independent clones were injected into C57BL/6 blastocycts. The chimeric animals were crossed to C57BL/6J mice, and the litters obtained from heterozygous crossings were genotyped through Southern blotting and PCR (Fig. 1B and C). Crossing of the heterozygous animals produced all genotypes in the expected Mendelian ratio. Out of 59 mice born in 7 litters, 16 homozygotes (27%), 28 heterozygotes (48%), and 15 wild-type (25%) mice were obtained.
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The epithelia of mice lacking periplakin appear normal. In wild-type neonatal mouse mouth epithelium, as represented by the dorsal lip and dorsal tongue epithelia, periplakin is distinctly present throughout the upper granular cell layer, at the cell-cell junctions, and along the plasma membrane of the flattened keratinocytes (Fig. 2A). For comparison, desmoplakin is present at all cell-cell junctions throughout these epithelia. The morphology of palate epithelium (Fig. 2B) and dorsal skin (Fig. 2C) of a wild-type mouse and a periplakin knockout littermate was studied through double labeling for periplakin and desmoplakin. The upper granular cell layer stained positive for periplakin in the wild-type mouse, but the absence of periplakin was obvious in the Ppl–/– littermate. Double-labeling for desmoplakin confirmed the normal appearance of epithelia lacking periplakin (panels d in Fig. 2B and C).
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Normal CEs develop in the absence of periplakin. CEs are stable structures of differentiated keratinocytes (41, 50). Envelopes were prepared from the dorsal skin of neonatal mice. From four litters obtained from heterozygous crossing, a pair of wild-type and knockout mice was randomly selected, and the CEs were prepared and examined by phase-contrast microscopy (Fig. 3). The CEs prepared from ppl–/– mice were indistinguishable from those of wild-type mice. Both strains of mice possessed a mixture of balloon-shaped and angular envelopes. Similarly, it has been reported that CEs prepared from involucrin–/– mice as well as envoplakin–/– mice are ultrastructurally indistinguishable from those isolated from normal mice (13, 34), but the lack of loricrin, although compensated by other proteins, results in quasinormal CEs (22).
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Absence of periplakin is not compensated through the altered level of other epidermal proteins. Since periplakin has been detected as a component of the CE, at the cell membranes associated with various adhesion structures, and in the cytoplasmic pool, it was of interest to determine how its absence will affect other epidermal proteins. We analyzed a litter of 10 mice obtained from a heterozygous crossing with three wild-type (+/+), four heterozygous (+/–), and three knockout (–/–) offspring, through the Western blotting analysis (Fig. 6). The complete absence of periplakin in knockout mice was confirmed. However, the level of plectin, desmoplakin, envoplakin, involucrin, and actin in each skin extract did not change appreciably with the genotype of the offspring, thus providing no evidence for a compensatory mechanism through the level of these proteins.
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DISCUSSION |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Clearly, as reported in this study or previously (13, 34), periplakin, envoplakin, and involucrin, when deleted through targeted inactivation of the corresponding genes in mice, are not crucial for CE formation and epithelial barrier function. The CE formation may be achieved through compensatory mechanisms. This has been demonstrated in loricrin-deficient mice, where an increased expression of members of the small proline-rich protein family and repetin are thought to compensate for the loricrin deficiency (28). Thus, not a single molecular constituent has been found thus far to be indispensable for CE integrity. Abundant but highly insoluble molecules, similar to periphilin, which we recently characterized through the yeast two-hybrid interaction, cDNA cloning, and overexpression in host cells (25), hold a potential to be indispensable for epithelial barrier function. In fact, we can speculate that periplakin, and perhaps also envoplakin and involucrin, may become cross-linked to the CE by default as a mechanism for disposing of these proteins during epithelial differentiation. Such a "dustbin" or "trashcan" hypothesis has been proposed (37), although a more organized model developed for the assembly of the CE does not support it (23).
Although periplakin was originally identified as a precursor of the CE in terminally differentiated epidermal keratinocytes (33, 42, 44), its expression has also been demonstrated in other tissues with a prominent epithelial component (4, 26). The yeast two-hybrid screening for periplakin interaction partners confirmed a specific binding of periplakin to keratin 8 and vimentin (26, 53). Transfection studies have shown that the overexpression of envoplakin resulted in the aggregate formation, but the overexpression of periplakin was able to rescue envoplakin from forming such aggregates and, instead, allowed it to resume its intermediate filament-associated localization (12). However, periplakin has been seen prominently aligned with the intermediate filaments only as a result of overexpression (24, 26). In cultured keratinocytes periplakin appears in a punctate cytoplasmic staining, and upon induction of differentiation, periplakin localizes to the cell-cell junctions and to the apical plasma membrane (33, 42). Periplakin was recently found in lens fiber cells, forming a cortical complex with ezrin, periaxin, and desmoyokin (49).
In epidermis, plectin is mainly localized to hemidesmosomes and displays staining along the basement membrane zone. Using a novel monoclonal antibody and carefully controlling the protocol for sample treatment, we recently showed that periplakin is also present in the basal cell layer in human neonatal foreskin epidermis, localizing along the basement membrane zone (1). The normal appearance of plectin in mouse epithelia in the absence of periplakin suggests independent interactions of these proteins with the hemidesmosomal transmembrane protein type XVII collagen/BP180 (1, 4, 6). Also, other novel protein-protein interactions, identified through yeast two-hybrid screening, suggest that periplakin serves other functions besides being a component of the CE (3). Unconventional, unexpected, and unexplained periplakin interaction partners include the intracellular domain of the hemidesmosomal transmembrane protein type XVII collagen/BPAG2/BP180 (1, 4), a G-protein receptor in brain (15), a tyrosine kinase, PKB/c-Akt, which is involved in regulation of apoptosis (53), and the 300-kDa mannose-6-phosphate receptor, involved in intracellular protein trafficking (48). In these reports, the overexpression of periplakin has been found to selectively inhibit µ-opioid receptor activation of G protein (15), modulate PKB signaling by binding and sequestration (53), and inhibit MPR-300-dependent endocytosis (48). Thus, although functional consequences for overexpression of periplakin have been suggested, the role of the endogenous periplakin in epithelial cells remains undisclosed.
In conclusion, the lack of a major phenotype for periplakin knockout mice suggests that the primary function of periplakin is not related to its physiological role as a component of the CE, but its role may be in pathological challenges which are not encountered by laboratory mice during their normal life span.
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ACKNOWLEDGMENTS |
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The Animal Models Core Facility in the Department of Dermatology and Cutaneous Biology, Thomas Jefferson University (Philadelphia, Pa.), is acknowledged for the production of mice. Specifically, the technical assistance of David Manion and Dominic Leperi in the generation of ES cell lines and maintenance of the animals is acknowledged, and Minna Mannikko is acknowledged for preliminary protein and genetic analysis. The skillful assistance of Sue Gotta and the Morphology Core in obtaining the microscopic images is also gratefully acknowledged. We thank John McGrath for preparing tissue samples for EM studies and Lyuben Marekov and Andrey Kalinin for providing the envoplakin antibody. We acknowledge discussions and the expert opinions of Fiona Watt, to whom periplakin knockout mice have been forwarded for generation of double and triple knockouts with envoplakin and involucrin null mice.
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FOOTNOTES |
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S.A., K.L., and Y.R. contributed equally to this work.
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