E‐cadherin is essential for in vivo epidermal barrier function by regulating tight junctions
Open accessAbstract
Cadherin adhesion molecules are key determinants of morphogenesis and tissue architecture. Nevertheless, the molecular mechanisms responsible for the morphogenetic contributions of cadherins remain poorly understood in vivo. Besides supporting cell-cell adhesion, cadherins can affect a wide range of cellular functions that include activation of cell signalling pathways, regulation of the cytoskeleton and control of cell polarity. To determine the role of E-cadherin in stratified epithelium of the epidermis, we have conditionally inactivated its gene in mice. Here we show that loss of E-cadherin in the epidermis in vivo results in perinatal death of mice due to the inability to retain a functional epidermal water barrier. Absence of E-cadherin leads to improper localization of key tight junctional proteins, resulting in permeable tight junctions and thus altered epidermal resistance. In addition, both Rac and activated atypical PKC, crucial for tight junction formation, are mislocalized. Surprisingly, our results indicate that E-cadherin is specifically required for tight junction, but not desmosome, formation and this appears to involve signalling rather than cell contact formation.
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Written from the paper’s full text.
TL;DR
Conditional loss of E-cadherin in mouse epidermis causes perinatal death from water loss due to impaired tight junction function, while desmosomes and cell-cell contacts remain largely intact. E-cadherin appears to regulate tight junction formation via signalling, involving mislocalization of activated aPKC and Rac rather than loss of adhesion per se.
Key findings
- K14-Cre/Ecad Fl/À mice died perinatally around 7–12 h after birth, lost about 9% body weight versus about 3% in controls, had increased haematocrit, and showed increased transepidermal water loss.
- The outside-in barrier remained functional, but inside-out permeability was impaired: biotin penetrated the granular layer to the stratum corneum, and epidermal resistance was three-fold lower in mutant skin than control skin, with dermal resistance not significantly affected (N=8 control, N=4 mutant; P=0.03).
- Tight junction components were mislocalized in mutant epidermis: claudin-1 was absent from the granular layer, claudin-4 showed punctate membrane distribution with less protein, and ZO-1 distribution was altered; occludin remained enriched at the membrane.
- Desmosomes formed normally and desmosomal cadherin expression was upregulated; P-cadherin was upregulated mainly in the basal layer. Activated aPKC was absent or largely diminished at suprabasal cell-cell borders, and Rac membrane localization was lost or diminished, while total activated Rac levels were unchanged.
Methods
- E-cadherin was conditionally inactivated in developing mouse epidermis using the Cre-loxP system with K14-Cre and floxed E-cadherin alleles, generating K14-Cre/Ecad Fl/Fl or K14-Cre/Ecad Fl/À mice; only data on K14-Cre/Ecad Fl/À mice are described because no phenotypic difference was found between lines.
- Analyses included RT-PCR, immunohistochemistry, Western blot, ultrastructural electron microscopy, weight and haematocrit measurements, TEWL measurement, lucifer yellow and toluidine blue penetration assays, intradermal biotin inside-out permeability assays, impedance analysis of skin biopsies, and Rac activation assays.
- Samples included newborn mice and embryonic stages E15.5, E16.5, and E18.5, depending on the assay.
Limitations
- The paper states that it remains unclear whether loss of E-cadherin impairs recruitment of activated aPKC to the membrane or whether aPKC is first recruited to adherens junctions and subsequently activated; it also notes that changes in activated Cdc42 may not be reflected by total Cdc42 levels.
- The paper states that the cornified layer may contribute to water loss in the mutants, although it is most likely not the primary cause.
- Evident from the text: many mechanistic conclusions are correlative and based on localization or protein-level changes rather than rescue experiments; impedance measurements used a small mutant sample (N=4); and only the K14-Cre/Ecad Fl/À line is described in the results.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
35 of 65 cited sources checked · 17 supported · 1 flagged · accuracy not yet measured
- Findingcitation
No difference in localization of desmosomal markers plakoglobin, desmocollin 2 and desmoglein 1/2 was observed between control and E-cadherin mutant mice.
“As described previously (Young et al, 2003;Tinkle et al, 2004), no difference in localization of desmosomal markers like plakoglobin, desmocollin 2 and desmoglein 1/2 was observed (Figure 3A).”
Quote in the paperSubstantial claim2 of 2 sources checked- cites Young et al, 2003 source
The ‘Ablation of E-cadherin alters epidermal differentiation’ section (page not provided) says desmoglein expression was comparable in mutant and control tissue, and the Figure 6 caption reports similar localization of desmoplakin. The copy also reports preserved desmosomes, but it does not establish unchanged localization for plakoglobin or desmocollin 2, or specify desmoglein 1/2. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites Tinkle et al, 2004 source
The Results (Fig. 2 F and G; page not available) report largely similar plakoglobin levels in wild-type and E-cadherin knockout epidermis, but do not explicitly establish unchanged localization. The Results also report increased desmosomal cadherins by immunofluorescence in knockout spinous layers (Fig. 2 E), rather than an unchanged signal for desmogleins 1/2. Our copy does not report a comparison for desmocollin 2. (LLM, conf=0.82)
Experimental — accuracy not yet measured
- Findingcitation
In control skin, biotin moves up to the stratum granulosum, where it is halted due to the presence of tight junctions, marked by occludin staining, between the cells of the granular layer.
“In control skin, biotin moves up to the stratum granulosum, where it is halted due to the presence of tight junctions, marked by occludin staining, between the cells of the granular layer (Furuse et al, 2002).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Furuse et al, 2002 source
- Premisecitation
Claudin-1 deficient mice also have an apparently normal cornified envelope.
“These mice also have an apparently normal cornified envelope.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Furuse et al, 2002 source
- Premisecitation
In vivo inactivation of claudin-1 results in epidermal water loss and ultimately neonatal death of mice.
“Their importance in maintaining the epidermal barrier was underscored by the observations that in vivo inactivation of the tight junctional membrane protein claudin-1 results in epidermal water loss and ultimately in neonatal death of the mice (Furuse et al, 2002).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Furuse et al, 2002 source
- Findingcitation
Claudin-4 is found at the membrane in the granular layer of the epidermis in control mice.
“Like occludin, claudin-4 is found at the membrane in the granular layer of the epidermis in control mice (Furuse et al, 2002).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Furuse et al, 2002 source
- Findingcitation
Rac was found at the membrane in control mice.
“Rac was found at the membrane in control mice, consistent with its function in cell-cell contact formation (Ehrlich et al, 2002).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Ehrlich et al, 2002 source
The passage describing Figure 2A reports RacGFP accumulating along newly contacting membranes, supporting membrane localization during cell-cell contact formation. The Experimental Procedures describe cultured MDCK cells, not control mice; the source therefore does not support the claim's population or condition. (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Premisecitation
In vivo, claudin-1 is essential for the epidermal water barrier.
“In vivo, claudin-1 is essential for the epidermal water barrier (Furuse et al, 2002).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Furuse et al, 2002 source
- Premisecitation
A previous paper did not reveal a lethal phenotype around birth in mice in which E-cadherin was deleted in the epidermis using K14-Cre.
“A previous paper did not reveal a lethal phenotype around birth in mice in which E-cadherin was deleted in the epidermis using K14-Cre (Tinkle et al, 2004).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Tinkle et al, 2004 source
- Premisecitation
This paper, and another study, in which E-cadherin was inactivated in the epidermis after birth, showed a gradual loss of hair in the E-cadherin mutant mice.
“This paper, and another study, in which E-cadherin was inactivated in the epidermis after birth, showed a gradual loss of hair in the E-cadherin mutant mice (Young et al, 2003;Tinkle et al, 2004).”
Quote in the paperNot a substantial claim2 of 2 sources checked - Findingown data
The E-cadherin gene was efficiently deleted from the epidermis of K14-Cre/Ecad Fl/À mice, as no RNA expression was observed.
“The E-cadherin gene was efficiently deleted from the epidermis of K14-Cre/Ecad Fl/À mice, as no RNA expression was observed (Figure 1B).”
Quote in the paperSubstantial claim - Findingreasoning
Catenin protein expression in the skin was not substantially altered in E-cadherin mutant mice.
“Catenin protein expression in the skin was not substantially altered (Figure 2B), most likely because of the upregulation of P-cadherin expression in the basal layer.”
Quote in the paperNot a substantial claim - Findingown data
Claudin-4 protein expression is less in K14-Cre/Ecad Fl/À mice.
“This appears to correlate with less protein expression in the K14-Cre/Ecad Fl/À mice (Figure 8B).”
Quote in the paperSubstantial claim - Findingown data
In K14-Cre/Ecad Fl/À mice, claudin-1 staining was absent from cells of the granular layer of the epidermis.
“Interestingly, in K14-Cre/Ecad Fl/À mice, claudin-1 staining was absent from cells of the granular layer of the epidermis (Figure 8A), which form the functional tight junctions.”
Quote in the paperSubstantial claim - Findingown data
In all K14-Cre/Ecad Fl/À mice, scaling of the upper ventral side occurs after a few hours.
“In all K14-Cre/Ecad Fl/À mice, scaling of the upper ventral side occurs after a few hours (Figure 5A).”
Quote in the paperNot a substantial claim - Findingown data
E-cadherin mutant mice lost around 9% of their body weight during their short lifespan in comparison to an average 3% in control mice.
“Weighing experiments showed that E-cadherin mutant mice lost around 9% of their body weight during their short lifespan in comparison to an average 3% in control mice (Figure 5B).”
Quote in the paperSubstantial claim - Findingown data
Phospho-aPKC was absent or largely diminished at cell-cell borders of the suprabasal layers in K14-Cre/Ecad Fl/À mice.
“More importantly, we found that phospho-aPKC was absent or largely diminished at cell-cell borders of the suprabasal layers in K14-Cre/Ecad Fl/À mice (Figure 9A).”
Quote in the paperSubstantial claim - Findingown data
Par3 is found at cell-cell contacts in all suprabasal layers of the epidermis.
“Par3 is found at cell-cell contacts in all suprabasal layers of the epidermis, and its distribution (Figure 9A) and amount of protein (Figure 9B) were not significantly altered in K14-Cre/Ecad Fl/À mice.”
Quote in the paperNot a substantial claim - Findingown data
Occludin is still enriched at the membrane in the granular layer of K14-Cre/Ecad Fl/À mice.
“Occludin is still enriched at the membrane in the granular layer of K14-Cre/ Ecad Fl/À mice (Figure 8A), implying that tight junctions are not completely disturbed in the absence of E-cadherin.”
Quote in the paperSubstantial claim - Findingown data
ZO-1 membrane staining was still observed in K14-Cre/Ecad Fl/À mice.
“ZO-1 membrane staining was still observed, indicating that the improper formation of epidermal tight junctions is not due to the inability to recruit ZO-1 to the membrane.”
Quote in the paperSubstantial claim - Findingown data
This aPKC phenotype was observed in 50% of the K14-Cre/Ecad Fl/À mice.
“This phenotype was observed in 50% of the K14-Cre/Ecad Fl/À mice.”
Quote in the paperNot a substantial claim - Findingown data
Altered distribution of ZO-1 at the cell surface, showing a more punctate pattern, was observed in the epidermis of K14-Cre/Ecad Fl/À mice.
“However, we did see altered distribution of ZO-1 at the cell surface, showing a more punctate pattern in the epidermis of K14-Cre/Ecad Fl/À mice (Figure 8A).”
Quote in the paperSubstantial claim - Findingown data
Absence of E-cadherin resulted in loss or largely reduced staining in the suprabasal layers for a-catenin, b-catenin and p120ctn.
“Absence of E-cadherin resulted in loss or largely reduced staining in the suprabasal layers for the cadherin-associated molecules a-catenin, b-catenin and p120 ctn (Figure 2A).”
Quote in the paperSubstantial claim - Findingown data
Loss of E-cadherin in the epidermis in vivo results in perinatal death of mice due to the inability to retain a functional epidermal water barrier.
“Here we show that loss of E-cadherin in the epidermis in vivo results in perinatal death of mice due to the inability to retain a functional epidermal water barrier.”
Quote in the paperSubstantial claim - Findingown data
A considerable increase in transepidermal water loss (TEWL) was measured in K14-Cre/Ecad Fl/À mice compared to control.
“Indeed, a considerable increase in transepidermal water loss (TEWL) was measured in the K14-Cre/Ecad Fl/À mice compared to control (Figure 5D).”
Quote in the paperSubstantial claim - Findingown data
Desmosomal cadherin expression was upregulated in E-cadherin mutant mice.
“Desmosomal cadherin expression was upregulated (Figure 3C), suggesting compensation for the loss of classical cadherins in the suprabasal layers.”
Quote in the paperSubstantial claim - Findingown data
E-cadherin was already almost completely absent in the epidermis of 15.5-day-old embryos (E15.5) in mutant mice.
“In addition, E-cadherin was already almost completely absent in the epidermis of 15.5-day-old embryos (E15.5), indicating efficient deletion during development of the epidermis (Figure 1C).”
Quote in the paperSubstantial claim - Findingown data
The dermal resistance was not significantly affected in mutant skin compared to control.
“A three-fold lower epidermal resistance was observed in mutant skin compared to control skin, whereas the dermal resistance was not significantly affected (Figure 7B).”
Quote in the paperSubstantial claim - Findingown data
An increased haematocrit of mutant mice was observed.
“An increased haematocrit of mutant mice was also observed (Figure 5C), indicating loss of fluids from the K14-Cre/Ecad Fl/À mice.”
Quote in the paperNot a substantial claim - Findingown data
No phenotypic difference was found between the two E-cadherin mutant lines.
“Since we have found no phenotypic difference between the two E-cadherin mutant lines, only data on the K14-Cre/Ecad Fl/À mice are described.”
Quote in the paperNot a substantial claim - Findingown data
Both Rac and activated atypical PKC are mislocalized upon loss of E-cadherin in the epidermis.
“In addition, both Rac and activated atypical PKC, crucial for tight junction formation, are mislocalized.”
Quote in the paperSubstantial claim - Findingown data
Western blot analysis of total skin lysates confirmed the absence of E-cadherin protein in knockout but not control skin.
“Western blot analysis of total skin lysates confirmed the absence of E-cadherin protein in knockout but not control skin (Figure 1D).”
Quote in the paperSubstantial claim - Findingown data
The basal staining pattern of aPKC was disturbed upon loss of E-cadherin, resulting in a patchy pattern instead of the relatively regular lining at the basal side of these cells.
“Surprisingly, this basal staining pattern was disturbed upon loss of E-cadherin, resulting in a patchy pattern instead of the relatively regular lining at the basal side of these cells (Figure 9A).”
Quote in the paperSubstantial claim - Findingown data
K14-Cre/Ecad Fl/À mice die perinatally around 7-12 h after birth.
“The K14-Cre/Ecad Fl/À mice die perinatally around 7-12 h after birth.”
Quote in the paperSubstantial claim - Findingown data
Only staining of the surface of the cornified layer was observed in both control and K14-Cre/Ecad Fl/À newborn mice using lucifer yellow.
“Only staining of the surface of the cornified layer was observed in both control and K14-Cre/Ecad Fl/À newborn mice (Figure 6A), indicating the presence of a functional stratum corneum.”
Quote in the paperSubstantial claim - Findingown data
Tight junction-like structures were observed in the granular layer of K14-Cre/Ecad Fl/À mice by conventional electron microscopy.
“This is also suggested by the observation of tight junction-like structures in the granular layer of K14-Cre/Ecad Fl/À mice by conventional electron microscopy (Supplementary Figure 3).”
Quote in the paperNot a substantial claim - Findingown data
No major difference in aPKC protein amounts was found between control and mutant.
“No major difference in protein amounts was found (Figure 9B).”
Quote in the paperNot a substantial claim - Findingown data
The skin was impermeable for both control and K14-Cre/Ecad Fl/À E18.5 embryos in toluidine blue penetration assays.
“The skin was impermeable for both control and K14-Cre/Ecad Fl/À E18.5 embryos (Figure 6B), indicating that the outside-in barrier is functional at this stage in the E-cadherin mutant embryos.”
Quote in the paperSubstantial claim - Findingown data
A slight decrease of total claudin-1 protein was observed in K14-Cre/Ecad Fl/À mice.
“A slight decrease of total claudin-1 protein was also observed (Figure 8B).”
Quote in the paperNot a substantial claim - Findingown data
Histological and ultrastructural analysis revealed no obvious defects in cell contacts in skin sections of control and K14-Cre/Ecad Fl/À mice.
“Importantly, histological and ultrastructural analysis revealed no obvious defects in cell contacts in skin sections of control and K14-Cre/Ecad Fl/À mice (Figure 4 and Supplementary Figure 1).”
Quote in the paperSubstantial claim - Findingown data
In control mice, phospho-aPKC antibodies stained cell-cell contacts, next to the epidermal-dermal junction.
“In control mice, phospho-aPKC antibodies stained cell-cell contacts, next to the epidermal-dermal junction, showing that the predominant total protein localization does not necessarily reflect the distribution of active forms.”
Quote in the paperSubstantial claim - Findingown data
Ultrastructural analysis showed the presence of well developed desmosomes in K14-Cre/Ecad Fl/À mice.
“Indeed, ultrastructural analysis showed the presence of well developed desmosomes in the K14-Cre/Ecad Fl/À mice (Figure 3B).”
Quote in the paperSubstantial claim - Findingown data
aPKC is highly concentrated at the epidermal-dermal junction in basal keratinocytes of control mice.
“Although aPKC forms a complex with Par3, its overall distribution was not similar to that of Par3 but, instead, was highly concentrated at the epidermal-dermal junction in basal keratinocytes of control mice.”
Quote in the paperNot a substantial claim - Findingown data
Macroscopic examination of K14-Cre/Ecad Fl/À mice did not reveal any blistering of the skin, even after rubbing.
“Macroscopic examination of the K14-Cre/Ecad Fl/À mice did not reveal any blistering of the skin, even after rubbing, suggesting no major changes in cell contact formation.”
Quote in the paperSubstantial claim - Findingown data
In K14-Cre/Ecad Fl/À epidermis, biotin penetrates the granular layer and is able to reach the stratum corneum.
“However, in K14-Cre/Ecad Fl/À epidermis, biotin penetrates the granular layer and is able to reach the stratum corneum (Figure 7A, left panel).”
Quote in the paperSubstantial claim - Findingown data
A three-fold lower epidermal resistance was observed in mutant skin compared to control skin.
“A three-fold lower epidermal resistance was observed in mutant skin compared to control skin, whereas the dermal resistance was not significantly affected (Figure 7B).”
Quote in the paperSubstantial claim - Findingown data
K14-Cre/Ecad Fl/À mice die of water loss.
“K14-Cre/Ecad Fl/À mice die of water loss.”
Quote in the paperSubstantial claim - Findingown data
Loss of E-cadherin did not substantially alter the amount of activated Rac in total skin lysates.
“Although cadherin engagement has been shown to directly activate Rac (Noren et al, 2001), we find that loss of E-cadherin did not substantially alter the amount of activated Rac in total skin lysates (Figure 9C), suggesting that E-cadherin is important for the recruitment of activated Rac to the membrane.”
Quote in the paperSubstantial claim - Findingown data
Altered localization of activated atypical PKC and the small GTPase Rac occurs in K14-Cre/Ecad Fl/À mice.
“Altered localization of activated atypical PKC and the small GTPase Rac in K14-Cre/Ecad Fl/À mice.”
Quote in the paperSubstantial claim - Findingown data
P-cadherin is only substantially upregulated in the basal layer in the absence of E-cadherin.
“However, P-cadherin is only substantially upregulated in the basal layer in the absence of E-cadherin and it may require cadherin expression in the suprabasal layers to support tight junctions.”
Quote in the paperNot a substantial claim - Findingown data
Phospho-aPKC was detected in total skin lysates of control and K14-Cre/Ecad Fl/À mice.
“It is not necessary for phosphorylation of aPKC per se because phospho-aPKC was detected in total skin lysates of control and K14-Cre/Ecad Fl/À mice (Figure 9B).”
Quote in the paperSubstantial claim - Findingown data
Tight junction formation is not completely disturbed in the absence of E-cadherin, since occludin is still normally expressed and tight junction-like structures are observed.
“Even tight junction formation is not completely disturbed since occludin is still normally expressed and tight junction-like structures are observed, indicating that E-cadherin is not generally required for proper positioning of all tight junctional components.”
Quote in the paperSubstantial claim - Findingown data
Adherens junctions expression is altered in K14-Cre/Ecad Fl/À mice.
“Adherens junctions expression is altered in K14-Cre/Ecad Fl/À mice.”
Quote in the paperSubstantial claim - Findingown data
Early loss of E-cadherin from the developing epidermis results in TEWL leading to perinatal death.
“In the present paper we show that E-cadherin contributes to the formation of the epidermal barrier of skin: early loss of E-cadherin from the developing epidermis results in TEWL leading to perinatal death.”
Quote in the paperSubstantial claim - Findingown data
Improper formation of tight junctions occurs in K14-Cre/Ecad Fl/À mice.
“Improper formation of tight junctions in K14-Cre/Ecad Fl/À mice.”
Quote in the paperSubstantial claim - Findingown data
Epidermal loss of E-cadherin does not affect the outside-in barrier.
“Epidermal loss of E-cadherin does not affect the outside-in barrier.”
Quote in the paperSubstantial claim - Findingnone given
In control mice, P-cadherin is most abundantly expressed around the hair follicles and only weakly in the interfollicular epidermis.
“In control mice, P-cadherin is most abundantly expressed around the hair follicles and only weakly in the interfollicular epidermis.”
Quote in the paperSubstantial claim - Findingown data
Cell-cell membrane association of the small GTPase Rac is greatly reduced in the absence of E-cadherin.
“A suggestion for the latter possibility comes from the observation that cell-cell membrane association of the small GTPase Rac is greatly reduced in the absence of E-cadherin (Figure 9).”
Quote in the paperNot a substantial claim - Findingown data
In the E-cadherin-deficient epidermis, P-cadherin expression is strongly increased in the basal cells of this area.
“However, in the E-cadherin-deficient epidermis, P-cadherin expression is strongly increased in the basal cells of this area.”
Quote in the paperSubstantial claim - Findingown data
The inability to form functional tight junctions in the absence of E-cadherin coincides with loss or largely reduced presence of activated aPKC from sites of cell-cell contacts.
“We find that the inability to form functional tight junctions in the absence of E-cadherin coincides with loss or largely reduced presence of activated aPKC from sites of cell-cell contacts (Figure 9).”
Quote in the paperSubstantial claim - Findingown data
Cdc42 is predominantly found in the cytoplasm of basal keratinocytes of control and mutant epidermis.
“Cdc42 is predominantly found in the cytoplasm of basal keratinocytes of control and mutant epidermis (Figure 9A), suggesting that E-cadherin is not required for Cdc42 function.”
Quote in the paperSubstantial claim - Findingown data
Tight junctions are functionally impaired in K14-Cre/Ecad Fl/À mice.
“Tight junctions are functionally impaired in K14-Cre/ Ecad Fl/À mice.”
Quote in the paperSubstantial claim - Findingown data
At least in stratifying epithelia, E-cadherin is not generally required for junction formation.
“The data show that at least in stratifying epithelia, E-cadherin is not generally required for junction formation.”
Quote in the paperSubstantial claim - Findingown data
Desmosomes are formed in the absence of E-cadherin.
“Desmosomes are formed in the absence of E-cadherin.”
Quote in the paperNot a substantial claim - Findingown data
Protein expression of desmosomal cadherins is also upregulated in E-cadherin-deficient epidermis.
“In addition, protein expression of desmosomal cadherins is also upregulated (Figure 3C).”
Quote in the paperSubstantial claim - Findingown data
We were unable to detect any obvious functional differences in the barrier function of the stratum corneum between control and K14-Cre/Ecad Fl/À mice.
“We were unable to detect any obvious functional differences in the barrier function of the stratum corneum between control and K14-Cre/Ecad Fl/À mice, indicating that the cornified layer is not disturbed and still constitutes a functional barrier.”
Quote in the paperSubstantial claim - Findingown data
The cell-cell membrane pattern of Rac was absent or largely diminished in suprabasal layers of K14-Cre/Ecad Fl/À mice.
“Interestingly, this cell-cell membrane pattern was absent or largely diminished in suprabasal layers of K14-Cre/Ecad Fl/À mice (Figure 9A).”
Quote in the paperSubstantial claim - Findingown data
E-cadherin is essential for appropriate tight junction formation in vivo.
“Our results do show for the first time that E-cadherin is essential for appropriate tight junction formation in vivo.”
Quote in the paperSubstantial claim - Findingown data
No differences in the levels of activated Rac were found between skin lysates of control and K14-Cre/Ecad Fl/À mice.
“However, no differences in the levels of activated Rac were found between skin lysates of control and K14-Cre/ Ecad Fl/À mice (Figure 9C), suggesting that E-cadherin is important for the recruitment of activated Rac to sites of cell-cell contact but not for its activation per se.”
Quote in the paperSubstantial claim - Interpretationown data
The absence of E-cadherin from the suprabasal layers was not compensated by the expression of other classical cadherins.
“These results suggested that the absence of E-cadherin from the suprabasal layers was not compensated by the expression of other classical cadherins.”
Quote in the paperSubstantial claim - Premisereasoning
Initial cell-cell adhesion mediated by the cadherin complex is a key step in setting up other cell junctions and epithelial polarity.
“Together, these data have led to a model in which initial cell-cell adhesion mediated by the cadherin complex is a key step in setting up other cell junctions and epithelial polarity.”
Quote in the paperSubstantial claim - Interpretationown data
The outside-in barrier is functional at E18.5 in E-cadherin mutant embryos.
“The skin was impermeable for both control and K14-Cre/Ecad Fl/À E18.5 embryos (Figure 6B), indicating that the outside-in barrier is functional at this stage in the E-cadherin mutant embryos.”
Quote in the paperSubstantial claim - Interpretationown data
The lethal phenotype of the E-cadherin mutant mice most likely results from water loss as a result of a disturbance in epidermal barrier function.
“Thus, the lethal phenotype of the E-cadherin mutant mice most likely results from water loss as a result of a disturbance in epidermal barrier function.”
Quote in the paperSubstantial claim - Premisecitation
Tight junctions are exclusively found in the granular layer of the epidermis.
“Tight junctions, previously thought to be absent in the epidermis, are exclusively found in the granular layer (Morita et al, 1998;Pummi et al, 2001;Brandner et al, 2002).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Interpretationown data
The improper formation of epidermal tight junctions is not due to the inability to recruit ZO-1 to the membrane.
“ZO-1 membrane staining was still observed, indicating that the improper formation of epidermal tight junctions is not due to the inability to recruit ZO-1 to the membrane.”
Quote in the paperSubstantial claim - Interpretationown data
Inappropriate localization of ZO-1 may contribute to altered tight junction function.
“Inappropriate localization of ZO-1 may thus contribute to altered tight junction function.”
Quote in the paperSubstantial claim - Interpretationown data
E-cadherin is not essential for desmosome formation in vivo.
“Thus, E-cadherin is not essential for desmosome formation in vivo.”
Quote in the paperSubstantial claim - Interpretationreasoning
The upregulation of P-cadherin in the basal layer in combination with an increase in desmosomal cadherins may explain why no obvious loss of cell-cell cohesion is observed in K14-Cre/Ecad Fl/À mice.
“The upregulation of P-cadherin in the basal layer in combination with an increase in desmosomal cadherins may explain why no obvious loss of cell-cell cohesion is observed in the K14-Cre/Ecad Fl/À mice.”
Quote in the paperSubstantial claim - Interpretationown data
The requirement of E-cadherin for tight junction formation appears to involve signalling rather than cell contact formation.
“Surprisingly, our results indicate that E-cadherin is specifically required for tight junction, but not desmosome, formation and this appears to involve signalling rather than cell contact formation.”
Quote in the paperSubstantial claim - Interpretationown data
The water loss seen in K14-Cre/Ecad Fl/À mice is directly related to increased tight junctional permeability.
“Together, these results strongly indicate that the water loss seen in K14-Cre/Ecad Fl/À mice is directly related to increased tight junctional permeability.”
Quote in the paperSubstantial claim - Interpretationown data
The stratum corneum is functional in K14-Cre/Ecad Fl/À newborn mice.
“Only staining of the surface of the cornified layer was observed in both control and K14-Cre/Ecad Fl/À newborn mice (Figure 6A), indicating the presence of a functional stratum corneum.”
Quote in the paperSubstantial claim - Interpretationown data
P-cadherin only compensates for the loss of E-cadherin in the basal layer.
“P-cadherin expression is upregulated (Figure 2B) but was still mainly found in the basal layer of the epidermis of E-cadherin mutant mice (Figure 2A), suggesting that P-cadherin only compensates for the loss of Ecadherin in the basal layer.”
Quote in the paperNot a substantial claim - Interpretationown data
Tight junctions are not completely disturbed in the absence of E-cadherin.
“Occludin is still enriched at the membrane in the granular layer of K14-Cre/ Ecad Fl/À mice (Figure 8A), implying that tight junctions are not completely disturbed in the absence of E-cadherin.”
Quote in the paperNot a substantial claim - Interpretationown data
This is consistent with our finding that loss of claudin-1 from the epidermal tight junctions, in combination with mislocalization of claudin-4, decreases epithelial resistance.
“This is consistent with our finding that loss of claudin-1 from the epidermal tight junctions, in combination with mislocalization of claudin-4, decreases epithelial resistance.”
Quote in the paperSubstantial claim - Interpretationown data
The malfunctioning of tight junctions is associated with inappropriate localization of activated aPKC and Rac.
“This is associated with inappropriate localization of activated aPKC and Rac.”
Quote in the paperSubstantial claim - Interpretationown data
Although the cornified layer may contribute to the water loss seen in K14-Cre/Ecad Fl/À mice, this is most likely not the primary cause.
“Although the cornified layer may contribute to the water loss seen in the K14-Cre/Ecad Fl/À mice, this is most likely not the primary cause.”
Quote in the paperSubstantial claim - Interpretationown data
The molecular basis of the leaky tight junctional barrier is most likely the aberrant or lack of incorporation of key tight junctional proteins, like claudin-1 and -4, and ZO-1, into junctions.
“The molecular basis of the leaky tight junctional barrier is most likely the aberrant or lack of incorporation of key tight junctional proteins, like claudin-1 and -4, and ZO-1, into junctions.”
Quote in the paperSubstantial claim - Interpretationown data
E-cadherin is not necessary for phosphorylation of aPKC per se.
“It is not necessary for phosphorylation of aPKC per se because phospho-aPKC was detected in total skin lysates of control and K14-Cre/Ecad Fl/À mice (Figure 9B).”
Quote in the paperSubstantial claim - Interpretationreasoning
Since the floxed E-cadherin mice in both studies were the same, the most likely difference is the K14-Cre mice used.
“Since the floxed E-cadherin mice in both studies were the same, the most likely difference is the K14-Cre mice used.”
Quote in the paperNot a substantial claim - Interpretationown data
The absence of activated aPKC from sites of epidermal tight junction formation offers a likely explanation for the inability of K14-Cre/Ecad Fl/À mice to form functional tight junctions.
“The absence of activated aPKC from sites of epidermal tight junction formation offers a likely explanation for the inability of K14-Cre/Ecad Fl/À mice to form functional tight junctions.”
Quote in the paperSubstantial claim - Premisecitation
Epithelial cells lacking ZO-1 can still incorporate claudins and occludin in tight junctions.
“In addition, epithelial cells lacking ZO-1 can still incorporate claudins and occludin in tight junctions (Umeda et al, 2004).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Umeda et al, 2004 source
- Interpretationown data
E-cadherin is important for the recruitment of activated Rac to the membrane.
“Although cadherin engagement has been shown to directly activate Rac (Noren et al, 2001), we find that loss of E-cadherin did not substantially alter the amount of activated Rac in total skin lysates (Figure 9C), suggesting that E-cadherin is important for the recruitment of activated Rac to the membrane.”
Quote in the paperSubstantial claim - Interpretationown data
E-cadherin is not generally required for proper positioning of all tight junctional components.
“Even tight junction formation is not completely disturbed since occludin is still normally expressed and tight junction-like structures are observed, indicating that E-cadherin is not generally required for proper positioning of all tight junctional components.”
Quote in the paperSubstantial claim - Interpretationreasoning
ZO-1 is no longer incorporated into tight junctions in the absence of E-cadherin.
“Although loss of E-cadherin does not result in absence of ZO-1 from the membrane, its distribution is dramatically altered, suggesting that it is no longer incorporated into tight junctions.”
Quote in the paperSubstantial claim - Interpretationown data
Loss of E-cadherin is partially compensated by P-cadherin in the basal layer.
“Loss of E-cadherin is partially compensated by P-cadherin in the basal layer (Figure 2).”
Quote in the paperSubstantial claim - Interpretationcitation
The loss of activated aPKC from cell-cell contacts is a direct effect of E-cadherin and not dependent on its ability to initiate and maintain cell-cell contacts.
“The latter observation seems to be a direct effect of E-cadherin and not dependent on its ability to initiate and maintain cell-cell contacts, as previous results in Drosophila suggested (Bilder et al, 2003;Tanentzapf and Tepass, 2003).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationown data
E-cadherin is not required for Cdc42 function.
“Cdc42 is predominantly found in the cytoplasm of basal keratinocytes of control and mutant epidermis (Figure 9A), suggesting that E-cadherin is not required for Cdc42 function.”
Quote in the paperNot a substantial claim - Interpretationreasoning
The observed TEWL in K14-Cre/Ecad Fl/À mice might thus be due to a failure to incorporate claudin-1 into tight junctions.
“The observed TEWL in K14-Cre/Ecad Fl/À mice might thus be due to a failure to incorporate claudin-1 into tight junctions.”
Quote in the paperSubstantial claim - Premisecitation
Overexpression of claudin-1 in MDCK cells results in a four-fold increase in transepidermal resistance.
“For example, overexpression of claudin-1 in MDCK cells results in a four-fold increase in transepidermal resistance, a measure of ion permeability (Inai et al, 1999).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Inai et al, 1999 source
- Interpretationcitation
E-cadherin regulates claudin-1, claudin-4 and ZO-1 localization by activating aPKC.
“Instead, our results suggest that E-cadherin regulates claudin-1, claudin-4 and ZO-1 localization by activating aPKC, implicated in tight junction formation in simple epithelial cells (Suzuki et al, 2002).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Suzuki et al, 2002 source
- Interpretationreasoning
P-cadherin is unable to substitute for E-cadherin in regulating tight junction formation.
“The results suggest that P-cadherin, although quite similar to Ecadherin, is unable to substitute for E-cadherin in regulating tight junction formation.”
Quote in the paperSubstantial claim
- May combine two claims. 40
- Classified as probably not a substantial claim. 35
May combine two claims.
FindingcitationBoth blistering and overgrowth phenotypes are not observed in K14-Cre/Ecad Fl/À mice.
“Both phenotypes are not observed in K14-Cre/Ecad Fl/À mice (Young et al, 2003;Tinkle et al, 2004;this paper).”
Quote in the paperSubstantial claim2 of 2 sources checked- cites Young et al, 2003 source
The “Generation of conditional E-cadherin-deficient mice” section identifies the mutants as Krox20-Cre; E-cadherin ±/lox, not K14-Cre/Ecad Fl/−. The “Reduced proliferation in hair follicles” section reports no detected increase in epidermal proliferation in those mutants, but the paper does not establish the absence of both blistering and overgrowth in the K14-Cre genotype. (LLM, conf=0.76)
Experimental — accuracy not yet measured - cites Tinkle et al, 2004 source
The Discussion (page unavailable) says older E-cadherin-null skin showed hyperproliferation and thickening, directly contrary to the claim that overgrowth was not observed. It also describes preservation of epidermal integrity, but that does not rescue the claim that neither phenotype occurred. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationZO-1 binds directly to a-catenin and this is considered an intermediate step in the formation of tight junctions.
“For example, the tight junctional marker ZO-1 binds directly to a-catenin and this is considered an intermediate step in the formation of tight junctions (Itoh et al, 1997).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Itoh et al, 1997 source
Probably not a substantial claim: may not pass S3 (load-bearing).
FindingcitationClaudin-1 is found at the membrane of all epidermal layers in control mice.
“Claudin-1 is not a specific marker for tight junctions in the epidermis but, as described previously (Furuse et al, 2002), is found at the membrane of all epidermal layers in control mice (Figure 8A).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Furuse et al, 2002 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe association of E-cadherin with the actin cytoskeleton is mediated by a-catenin linked to the cadherin via b-catenin.
“The association of E-cadherin with the actin cytoskeleton is mediated by a-catenin that is linked to the cadherin via b-catenin (Rimm et al, 1995).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Rimm et al, 1995 source
The Abstract (p. 8813) reports that α-catenin binds F-actin and that β-catenin can bind the α-catenin–actin complex. It proposes α-catenin as a tether at E-cadherin-mediated contacts, but does not establish the claimed β-catenin link to E-cadherin; it also presents the tethering mechanism as a model rather than a settled fact. (LLM, conf=0.85)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationMice deficient for the tight junctional protein claudin-1 also show extensive water loss, appear red, shiny and wrinkled, and die within the same time frame as E-cadherin mutant mice.
“Interestingly, mice deficient for the tight junctional protein claudin-1 also show extensive water loss, appear red, shiny and wrinkled, and die within the same time frame as our mutant mice negative for E-cadherin in the epidermis (Furuse et al, 2002).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Furuse et al, 2002 source
The Results sections on postnatal lethality and epidermal barrier impairment report that claudin-1–deficient mice developed wrinkled skin, had excessive transepidermal water loss, and died within one day of birth (page unavailable). The paper does not describe them as red or shiny. The comparison with the citing authors’ E-cadherin mutants depends on the citing authors’ own findings, not this source. (LLM, conf=0.87)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationIn vitro studies have shown that E-cadherin is necessary for adherens junction formation and its adhesive activity is crucial for assembly of desmosomes, gap junctions and tight junctions.
“In vitro studies have shown that E-cadherin is not only necessary for adherens junction formation but its adhesive activity is also crucial for the assembly of other junctional complexes such as desmosomes, gap junctions and tight junctions (Gumbiner et al, 1988;Musil et al, 1990;Watabe et al, 1994).”
Quote in the paperSubstantial claim3 of 3 sources checked- cites Gumbiner et al, 1988 source
The paper identifies uvomorulin as E-cadherin, and its discussion concludes that formation of adherens junctions, desmosomes, and tight junctions similarly depends on uvomorulin function. It does not address gap-junction assembly, so that part of the claim is unsupported by this source. The supplied passages do not give a page number for the discussion. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites Musil et al, 1990 source
The Results (p. 2083) show that disrupting L-CAM-mediated cell adhesion inhibits a change associated with functional gap junctions; the paper also reports that introducing L-CAM corrected a gap-junction communication defect. This supports a role for cell adhesion in gap-junction formation or function, but the cited paper does not establish the claimed necessity for adherens-junction formation or for assembly of desmosomes and tight junctions. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites Watabe et al, 1994 source
The study reports that activating E-cadherin in PC9 cells produced adherens junctions, tight junctions and desmosomes (p. 247), and its Discussion calls cadherin-mediated contact a prerequisite for forming the latter two (pp. 252–253). But it does not show that E-cadherin's adhesive activity is crucial for gap-junction assembly: the Introduction (p. 247) only says that introducing a cadherin into cadherin-deficient cells enhances gap-junction formation. (LLM, conf=0.85)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationExperiments in Drosophila have shown that mutations in junctional proteins affect junction formation and disturb epithelial polarity, and polarity mutants affect junction formation.
“Indeed, experiments in Drosophila have shown that mutations in junctional proteins not only affect junction formation but also disturb epithelial polarity, whereas polarity mutants have a profound effect on junction formation as well (Cox et al, 1996;Muller and Wieschaus, 1996;Tanentzapf et al, 2000).”
Quote in the paperSubstantial claim3 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationE-cadherin is important for tissue morphogenesis and polarity.
“E-cadherin is important for tissue morphogenesis and polarity (Larue et al, 1994).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Larue et al, 1994 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationZO-1 interacts with the C-terminus of all claudins and occludin.
“However, such a model does not explain why specifically claudin-1, but not claudin-4 or occludin, is lacking from the granular layer whereas ZO-1 interacts with the C-terminus of all claudins and occludin (Fanning et al, 1998;Itoh et al, 1999).”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites Fanning et al, 1998 source
The Results (page not provided) report that ZO-1 binds a fusion protein containing the C-terminal region of occludin. The paper does not report interactions with claudins, so it does not support the claim about all claudins. (LLM, conf=0.90)
Experimental — accuracy not yet measured - cites Itoh et al, 1999 source
The Results (page unavailable) show that ZO-1 binds the C-terminal regions of claudin-1 through claudin-8, which includes claudin-1 and claudin-4. The paper also reports binding between ZO-1 and the C-terminal tail of occludin. But it describes at least 16 claudin family members and does not establish binding to all of them. (LLM, conf=0.89)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationRac activity has been implicated in the regulation of tight junction gate and fence function.
“In addition, Rac activity has been implicated in the regulation of tight junction gate and fence function (Jou et al, 1998).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Jou et al, 1998 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThese authors did observe a slight disturbance in the epidermal barrier but have not examined tight junctional markers and function.
“Nevertheless, these authors did observe a slight disturbance in the epidermal barrier but have not examined tight junctional markers and function.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Tinkle et al, 2004 source
The Results report reduced filaggrin and loricrin in E-cadherin-null epidermis and say these changes were suggestive of a barrier defect that was likely mild. The paper does not report a direct barrier-function measurement, so “observed” overstates that inference. Its reported junctional analyses concern adherens junctions and desmosomes, not tight-junction markers or function. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe discovery of tight junctions and their importance in the epidermal water barrier came as a surprise.
“The discovery of tight junctions and their importance in the epidermal water barrier therefore came as a surprise (Brandner et al, 2002;Furuse et al, 2002).”
Quote in the paperNot a substantial claim1 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe stratum corneum consists of dead keratin-filled cells embedded in a lipid matrix, providing a tough insoluble layer that separates the outside from the inside.
“This layer consists of dead keratin-filled cells embedded in a lipid matrix, thus providing a tough insoluble layer that separates the outside from the inside (Nemes and Steinert, 1999).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Nemes and Steinert, 1999 source
Classified as probably not a substantial claim.
PremisecitationInactivation of a-catenin in the epidermis resulted in severe blistering and overgrowth.
“Inactivation of a-catenin in the epidermis resulted in severe blistering and overgrowth (Vasioukhin et al, 2001).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Vasioukhin et al, 2001 source
The discussion reports uncontrolled growth and large epidermal masses after α-catenin ablation, supporting the overgrowth claim. Figure 2 reports impaired intercellular junctions in the knockout epidermis, but the passages found do not report severe blistering; that part is unsupported. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
InterpretationcitationGrowth regulation may be a cadherin-independent function of a-catenin.
“Alternatively, growth regulation may be a cadherin-independent function of a-catenin (Vasioukhin et al, 2001).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Vasioukhin et al, 2001 source
The Discussion (page unavailable in our copy) says α-catenin’s effects on hyperproliferation can be separated from its effects on cell–cell adhesion, supporting a possible growth-regulatory role beyond adhesion. But the paper also links the altered growth signaling to an E-cadherin/β-catenin complex with IRS-1; it does not establish that growth regulation is independent of cadherin itself. (LLM, conf=0.83)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn vitro studies using mostly simple epithelial cells have indicated that E-cadherin-mediated adhesion is a necessary prerequisite for the formation of other cell junctions, such as desmosomes, gap junctions and tight junctions.
“In vitro studies using mostly simple epithelial cells have indicated that E-cadherin-mediated adhesion is a necessary prerequisite for the formation of other cell junctions, such as desmosomes, gap junctions and tight junctions (Gumbiner et al, 1988;Musil et al, 1990;Watabe et al, 1994).”
Quote in the paperNot a substantial claim3 of 3 sources checked- cites Gumbiner et al, 1988 source
The Abstract (p. 1575) reports that blocking uvomorulin, also identified as E-cadherin, similarly inhibited formation of desmosomes and tight junctions in cultured MDCK epithelial cells. It does not report testing gap junction formation, so that part of the citing sentence is not supported by this paper. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites Musil et al, 1990 source
The Results (p. 2083) show that introducing L-CAM into S180 cells increased gap-junction formation and communication, while disrupting L-CAM-mediated adhesion inhibited connexin43 processing. The Discussion says strong cell association *may* be important for gap-junction formation. The paper does not establish E-cadherin-mediated adhesion as a necessary prerequisite, or address desmosome and tight-junction formation as the claim states. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites Watabe et al, 1994 source
The Introduction (pp. 247–248) describes cadherins as prerequisites for epithelial junctional complexes, and the Discussion (p. 252) presents evidence that E-cadherin-mediated contact precedes tight-junction and desmosome formation. For gap junctions, however, the paper says cadherin introduction enhances their formation; it does not establish E-cadherin-mediated adhesion as necessary for them. (LLM, conf=0.84)
Experimental — accuracy not yet measured
May combine two claims.
Findingown dataE-cadherin staining was negative in the newborn epidermis of mutant mice, whereas E-cadherin staining was found in all layers of the epidermis in newborn control mice.
“Indeed, staining for E-cadherin was negative in the newborn epidermis of mutant mice, whereas E-cadherin staining was found as expected in all layers of the epidermis in the skin of newborn control mice (Figure 1C).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn K14-Cre/Ecad Fl/À mice, claudin-4 localization is still confined to the granular layer but its distribution on the membrane is altered, showing a more punctate staining pattern.
“Although its localization is still confined to the granular layer in K14-Cre/Ecad Fl/À mice, its distribution on the membrane is altered, showing a more punctate staining pattern.”
Quote in the paperSubstantial claimMay combine two claims.
Findingnone givenThe mutant skin appears more red and shiny than that of control littermates, and has a parchmentlike resemblance.
“The mutant skin appears more red and shiny than that of their control littermates, and has a parchmentlike resemblance.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataPartial penetration of toluidine blue is observed around the paws and the ventral side in control E16.5 embryos and this pattern is similar for K14-Cre/Ecad Fl/À E16.5 embryos.
“Indeed, partial penetration of toluidine blue is observed around the paws and the ventral side in control E16.5 embryos and this pattern is similar for K14-Cre/Ecad Fl/À E16.5 embryos (Figure 6B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataK14-Cre/Ecad Fl/Fl and K14-Cre/Ecad Fl/À mice both died within 1 day after birth.
“This resulted in either K14-Cre/Ecad Fl/Fl or K14-Cre/Ecad Fl/À mice (Figure 1A) that both died within 1 day after birth.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataDifferentiation markers and proliferation appeared normal in K14-Cre/Ecad Fl/À mice.
“Differentiation markers and proliferation appeared normal (Supplementary Figure 2).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataP-cadherin expression is upregulated in E-cadherin mutant mice but still mainly found in the basal layer of the epidermis.
“P-cadherin expression is upregulated (Figure 2B) but was still mainly found in the basal layer of the epidermis of E-cadherin mutant mice (Figure 2A), suggesting that P-cadherin only compensates for the loss of Ecadherin in the basal layer.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAbsence of E-cadherin leads to improper localization of key tight junctional proteins, resulting in permeable tight junctions and altered epidermal resistance.
“Absence of E-cadherin leads to improper localization of key tight junctional proteins, resulting in permeable tight junctions and thus altered epidermal resistance.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe distribution and amount of Par3 protein were not significantly altered in K14-Cre/Ecad Fl/À mice.
“Par3 is found at cell-cell contacts in all suprabasal layers of the epidermis, and its distribution (Figure 9A) and amount of protein (Figure 9B) were not significantly altered in K14-Cre/Ecad Fl/À mice.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingnone givenOur mice lack whiskers despite the presence of hair follicles.
“This fits with the observation that our mice lack whiskers despite the presence of hair follicles (not shown).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataE-cadherin loss does not alter the distribution of Par3, which is still found at sites of cell-cell contacts in the epidermis.
“However, E-cadherin loss did not alter the distribution of Par3, which is still found at sites of cell-cell contacts in the epidermis.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataLoss of E-cadherin does not result in absence of ZO-1 from the membrane, but its distribution is dramatically altered.
“Although loss of E-cadherin does not result in absence of ZO-1 from the membrane, its distribution is dramatically altered, suggesting that it is no longer incorporated into tight junctions.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataNormal structure and cell-cell contacts are present in K14-Cre/Ecad Fl/À mice.
“Normal structure and cell-cell contacts in K14-Cre/Ecad Fl/À mice.”
Quote in the paperSubstantial claimMay combine two claims.
Findingnone givenClaudin-1, but not claudin-4 or occludin, is lacking from the granular layer in the absence of E-cadherin.
“However, such a model does not explain why specifically claudin-1, but not claudin-4 or occludin, is lacking from the granular layer whereas ZO-1 interacts with the C-terminus of all claudins and occludin (Fanning et al, 1998;Itoh et al, 1999).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataDesmosomes are abundantly present in the absence of E-cadherin, and desmosomal markers appear to have their normal differentiation pattern within the epidermis.
“Desmosomes are abundantly present in the absence of E-cadherin, and desmosomal markers appear to have their normal differentiation pattern within the epidermis.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingnone givenCdc42 expression appears to be confined to the basal layer and is not altered by the loss of E-cadherin.
“However, this is perhaps unlikely in the upper layers of the epidermis, since Cdc42 expression appears to be confined to the basal layer and is not altered by the loss of E-cadherin.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataLoss of E-cadherin in the epidermis alters the permeability of tight junctions resulting in decreased epithelial resistance.
“Our results clearly show that loss of E-cadherin in the epidermis alters the permeability of tight junctions (Figure 7A) resulting in decreased epithelial resistance (Figure 7B).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe activity of the Par3/Par6/aPKC polarity protein complex has been implicated in the formation of tight junctions in simple epithelia.
“The activity of the Par3/Par6/aPKC polarity protein complex has been implicated in the formation of tight junctions in simple epithelia (Macara, 2004).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Macara, 2004 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationActivation of the Par3/Par6/aPKC complex depends on the formation of cell-cell contacts.
“Its activation depends on the formation of cell-cell contacts (Yamanaka et al, 2001) and Armadillo, the fly b-catenin homologue, is important for proper localization of this complex in Drosophila (Bilder et al, 2003;Tanentzapf and Tepass, 2003).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Yamanaka et al, 2001 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe size and ion selectivity of tight junctions depends on the type and levels of expression of claudins.
“The size and ion selectivity of tight junctions is variable within different tissues and depends on the type and levels of expression of claudins, four span transmembrane molecules, which constitute the tight junctional paired strands (Inai et al, 1999;Colegio et al, 2003).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
Interpretationown dataE-cadherin is specifically required for tight junction formation but not desmosome formation in the epidermis.
“Surprisingly, our results indicate that E-cadherin is specifically required for tight junction, but not desmosome, formation and this appears to involve signalling rather than cell contact formation.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitationp120ctn binds directly to the cadherin and regulates the stability of the cadherin complex at the cell surface.
“Another catenin, p120 ctn , also binds directly to the cadherin and regulates the stability of the cadherin complex at the cell surface (Reynolds and Roczniak-Ferguson, 2004).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Reynolds and Roczniak-Ferguson, 2004 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationUpon establishing cell-cell adhesion, cadherins cluster in adherens junctions, which associate with the actin cytoskeleton.
“Upon establishing cell-cell adhesion, cadherins cluster in specialized cell junctions, known as adherens junctions, which associate with the actin cytoskeleton (Gottardi et al, 2002).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Gottardi et al, 2002
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Interpretationown dataEven though tight junction formation is not completely disturbed, key components are not properly incorporated, which likely underlies the functional impairment of tight junctions.
“Overall, our results show that even though tight junction formation is not completely disturbed, key components are not properly incorporated, which likely underlies the functional impairment of tight junctions.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationActivation of the Par3/Par6/aPKC complex is achieved by binding to Cdc42, resulting in phosphorylation and activation of aPKC.
“Activation of the Par3/Par6/aPKC complex is achieved by binding to the small GTPase Cdc42, resulting in the phosphorylation and activation of aPKC (Joberty et al, 2000;Lin et al, 2000).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe Par3/Par6/aPKC complex localizes to the apical junctional complex in Drosophila and to tight junctions in mammalian epithelial cells.
“One of these polarity complexes consists of the Par3/ Par6/atypicalPKC (aPKC) complex, which localizes to the apical junctional complex in Drosophila and to tight junctions in mammalian epithelial cells (Nelson, 2003).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Nelson, 2003 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationJunctional complex assembly coincides with the establishment of cell polarity and enrichment of polarity protein complexes at cell junctions.
“This junctional complex assembly coincides with the establishment of cell polarity and enrichment at the cell junctions of several protein complexes known to be essential for polarity, suggesting an intimate relationship between junction formation and polarity (Nelson, 2003).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Nelson, 2003 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationTwo classical cadherins are expressed within the epidermis: P-cadherin confined to the basal layer, and E-cadherin found in all epidermal cell layers.
“Two classical cadherins are expressed within the epidermis: P-cadherin, which is confined to the basal layer, and E-cadherin found in all epidermal cell layers (Jensen et al, 1997).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Jensen et al, 1997 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationArmadillo, the fly b-catenin homologue, is important for proper localization of the Par3/Par6/aPKC complex in Drosophila.
“Its activation depends on the formation of cell-cell contacts (Yamanaka et al, 2001) and Armadillo, the fly b-catenin homologue, is important for proper localization of this complex in Drosophila (Bilder et al, 2003;Tanentzapf and Tepass, 2003).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationTight junctions act as selective permeability barriers and form a fence separating the apical membrane domain from the basolateral domain in simple epithelial cells.
“Tight junctions act as selective permeability barriers but also form a fence that physically separates the apical membrane domain from the basolateral domain in simple epithelial cells (Anderson et al, 2004).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Anderson et al, 2004 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDesmosomes provide tissues with stable and strong cell-cell adhesion.
“Desmosomes provide tissues with stable and strong cell-cell adhesion (Getsios et al, 2004).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Getsios et al, 2004 source
May combine two claims.
Interpretationown dataTight junctions are either absent or are no longer properly functioning in E-cadherin mutant skin.
“This suggested that tight junctions are either absent or are no longer properly functioning in E-cadherin mutant skin.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataMaturation of the cornified layer developed normal in the absence of E-cadherin, resulting in a properly functioning outside-in barrier.
“We therefore conclude that maturation of the cornified layer developed normal in the absence of E-cadherin, resulting in a properly functioning outside-in barrier.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationClaudin-6 overexpression in the skin disturbs barrier function.
“In addition, claudin-6 overexpression in the skin also disturbs barrier function (Turksen and Troy, 2002).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Turksen and Troy, 2002 source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe Rac activation assays were repeated three times.
“Experiments were repeated three times.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataE-cadherin is important for the recruitment of activated Rac to sites of cell-cell contact but not for its activation per se.
“However, no differences in the levels of activated Rac were found between skin lysates of control and K14-Cre/ Ecad Fl/À mice (Figure 9C), suggesting that E-cadherin is important for the recruitment of activated Rac to sites of cell-cell contact but not for its activation per se.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThe effect of E-cadherin loss on the epidermal barrier is not due to a loss of cell contact formation or altered epidermal differentiation.
“Surprisingly, this effect is not due to a loss of cell contact formation or altered epidermal differentiation.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationRac can bind to Par6 and thus potentially activate aPKC.
“It has been shown that Rac can bind to Par6 and thus potentially activate aPKC (Johansson et al, 2000;Lin et al, 2000).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
InterpretationreasoningThe effect of E-cadherin on tight junction formation is not simply the result of cell adhesion but rather seems to arise from signalling, most likely by recruitment of the small GTPase Rac and atypical PKC to sites of cell-cell contact.
“Overall, an important implication of our work is that this effect of E-cadherin on tight junction formation is not simply the result of cell adhesion but rather seems to arise from signalling, most likely by recruitment of the small GTPase Rac and atypical PKC to sites of cell-cell contact.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningThe increased expression of P-cadherin and desmosomal cadherins may explain why no blistering occurs and why cell contact formation appears normal in newborn epidermis.
“The increased expression of these two adhesive systems may explain why no blistering occurs and why cell contact formation appears normal in newborn epidermis (Figure 4).”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataIn our K14-cre/Ecad Fl/À mice, E-cadherin is already almost completely absent at E15.5 shortly before the onset of barrier formation, perhaps explaining why loss of E-cadherin has more dramatic consequences in our mice.
“In our K14-cre/Ecad Fl/À mice, E-cadherin is already almost completely absent at E15.5 (Figure 1C) shortly before the onset of barrier formation (Hardman et al, 1998), perhaps explaining why loss of E-cadherin has more dramatic consequences in our mice.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Hardman et al, 1998 source
Probably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningP-cadherin may require cadherin expression in the suprabasal layers to support tight junctions.
“However, P-cadherin is only substantially upregulated in the basal layer in the absence of E-cadherin and it may require cadherin expression in the suprabasal layers to support tight junctions.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMost data point to a role for Cdc42 as the small GTPase that activates the aPKC/Par3/Par6 complex.
“Most data point to a role for Cdc42 as the small GTPase that activates the aPKC/Par3/Par6 complex (Macara, 2004).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Macara, 2004 source
May combine two claims.
Interpretationown dataThe cornified layer is not disturbed and still constitutes a functional barrier in K14-Cre/Ecad Fl/À mice.
“We were unable to detect any obvious functional differences in the barrier function of the stratum corneum between control and K14-Cre/Ecad Fl/À mice, indicating that the cornified layer is not disturbed and still constitutes a functional barrier.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataE-cadherin is essential for activation of aPKC at the appropriate localization or for recruitment of activated forms to sites of cell-cell contact.
“Thus, E-cadherin is essential for activation of aPKC at the appropriate localization or for recruitment of activated forms to sites of cell-cell contact.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningThe upregulation of P-cadherin may also be sufficient to confer normal growth and differentiation properties to the basal epidermal keratinocytes in the absence of E-cadherin.
“The upregulation of P-cadherin may also be sufficient to confer normal growth and differentiation properties to the basal epidermal keratinocytes in the absence of E-cadherin.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataEssential tight junctional components are not properly targeted to tight junctions, resulting in malfunctioning of these structures.
“Instead, we find that essential tight junctional components are not properly targeted to tight junctions, resulting in malfunctioning of these structures.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe ability to initiate and maintain cell-cell contacts is considered key to this E-cadherin function.
“The ability to initiate and maintain cell-cell contacts is considered key to this E-cadherin function (Nelson, 2003).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Nelson, 2003 source
Probably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningRac may mediate E-cadherin-induced recruitment or activation of aPKC at cell-cell contacts in the epidermis.
“We propose that Rac may mediate E-cadherin-induced recruitment or activation of aPKC at cell-cell contacts in the epidermis.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationClaudins determine size and ion specificity of tight junctional barriers.
“Claudins determine size and ion specificity of tight junctional barriers.”
Quote in the paperSubstantial claim
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In E-cadherin-deficient SG2, TJ markers ZO-1 and occludin lose their continuous and linear apical distribution and instead show a more punctate pattern at cellular interfaces with many breaks.
“Moreover, the TJ markers ZO-1 and occludin lost their continuous and linear apical distribution in Ecadepi−/− SG2. Instead, these proteins showed a more punctate pattern at cellular interfaces, revealing many breaks (Fig. 3d), thus explaining why in vivo TJ barrier function is disturbed upon loss of E-cadherin10.”
From E-cadherin integrates mechanotransduction and EGFR signaling to control junctional tissue polarization and tight junction positioning (2017) · cites this paper as [10]
In “Increased permeability of tight junctions in the absence of E-cadherin” (page unavailable), the paper reports punctate ZO-1 staining in E-cadherin-deficient epidermis and impaired tight-junction function. It does not report the claimed punctate pattern or many breaks for occludin; instead, it says occludin remains enriched at the membrane in the granular layer. The paper also does not specify SG2 or describe a lost continuous, linear apical distribution. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn E-cadherin-deficient spinous layers, ZO-1 and occludin also show a punctate intercellular contact pattern, indicating premature formation of non-functional TJ-like structures.
“Interestingly, this punctate intercellular contact pattern of ZO-1 and occludin was also observed in Ecadepi−/− spinous layers, indicating premature formation of non-functional TJ-like structures (Fig. 3d, f; Supplementary Fig. 3e; ref. 10).”
From E-cadherin integrates mechanotransduction and EGFR signaling to control junctional tissue polarization and tight junction positioning (2017) · cites this paper as [10]
The section “Increased permeability of tight junctions in the absence of E-cadherin” reports a more punctate ZO-1 pattern in E-cadherin-deficient epidermis and impaired tight-junction function. It does not report punctate occludin in spinous layers or conclude that non-functional TJ-like structures form prematurely; it describes occludin as enriched at the membrane in the granular layer. (LLM, conf=0.88)
Experimental — accuracy not yet measuredA functional SC barrier is first formed in dorsal epidermis at embryonic day (E)16.5, spreading only to the ventral side one day later.
“A functional SC barrier is first formed in dorsal epidermis at embryonic day (E)16.5, spreading only to the ventral side one day later10, 20.”
From E-cadherin integrates mechanotransduction and EGFR signaling to control junctional tissue polarization and tight junction positioning (2017) · cites this paper as [10]
The section “The outside-in barrier is functional in K14-Cre/Ecad Fl/− mice” (page not supplied) reports dye penetration on the ventral side at E16.5, consistent with a barrier forming first elsewhere. It reports impermeability at E18.5 but does not establish that the barrier reached the ventral side exactly one day after E16.5. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe increased EGFR activity after E-cadherin loss is not associated with enhanced proliferation in vitro or in vivo.
“Interestingly, this increased activity was not associated with enhanced proliferation in vitro or in vivo (ref. 10; Supplementary Fig. 7g).”
From E-cadherin integrates mechanotransduction and EGFR signaling to control junctional tissue polarization and tight junction positioning (2017) · cites this paper as [10]
The 'Cell-cell contacts are maintained in the absence of E-cadherin' section (page unavailable) reports that proliferation appeared normal in the E-cadherin-deficient mouse epidermis, supporting the in vivo part. The cited paper does not establish the in vitro proliferation result or link the proliferation finding to increased EGFR activity; the citing sentence also points to its own Supplementary Fig. 7g. (LLM, conf=0.86)
Experimental — accuracy not yet measuredLoss of vinculin in the epidermis does not affect either apical ZO-1 positioning or F-actin distribution in SG2 and does not result in major barrier defects in vivo, as vinculinepi−/− mice are viable, unlike Ecadepi−/− mice generated using the same K14-Cre line.
“In contrast, loss of vinculin in the epidermis did not affect either apical ZO-1 positioning or F-actin distribution in SG2 and did not result in major barrier defects in vivo, as vinculinepi−/− mice are viable, unlike Ecadepi−/− mice generated using the same K14-Cre line10.”
From E-cadherin integrates mechanotransduction and EGFR signaling to control junctional tissue polarization and tight junction positioning (2017) · cites this paper as [10]
Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
In the epidermis, loss of E-cadherin expressed in all viable layers interferes with the TJ barrier, resulting in perinatal death.
“In the epidermis loss of E-cadherin expressed in all viable layers interferes with the TJ barrier, resulting in perinatal death10.”
From E-cadherin integrates mechanotransduction and EGFR signaling to control junctional tissue polarization and tight junction positioning (2017) · cites this paper as [10]
Desmosomes, considered an important mechanical unit, are formed in E-cadherin−/− keratinocytes.
“This was surprising as desmosomes, considered an important mechanical unit, are formed in these cells10, 23.”
From E-cadherin integrates mechanotransduction and EGFR signaling to control junctional tissue polarization and tight junction positioning (2017) · cites this paper as [10]
In vivo, loss of epidermal vinculin does not result in perinatal lethality, unlike loss of E-cadherin.
“In vivo, loss of epidermal vinculin did not result in perinatal lethality unlike loss of E-cadherin10.”
From E-cadherin integrates mechanotransduction and EGFR signaling to control junctional tissue polarization and tight junction positioning (2017) · cites this paper as [10]
E-cadherin controls the polarized localization and activity status of suprabasal EGFR, which is uncoupled from growth.
“In conclusion, E-cadherin controls the polarized localization and activity status of suprabasal EGFR, which is uncoupled from growth10.”
From E-cadherin integrates mechanotransduction and EGFR signaling to control junctional tissue polarization and tight junction positioning (2017) · cites this paper as [10]
The ‘Increased permeability of tight junctions’ section reports E-cadherin-dependent localization of activated aPKC and Rac in suprabasal epidermis, not EGFR. A search of our copy for EGFR and epidermal growth factor receptor found no passage addressing EGFR localization, activity, or whether its activity is uncoupled from growth. No page numbers were available for these passages. (LLM, conf=0.76)
Experimental — accuracy not yet measured
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Self-citationE-cadherin and P-cadherin have partially redundant roles in human epidermal stratification
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Flagged first, then by citations
Research works printed but not linked: 1
- Gottardi CJ, Niessen CM, Gumbiner BM (2002) The adherens junction. In Cell Adhesion, The Frontiers in Molecular Biology Series, Hames BD, Glover DM, Beckerle M (eds). chap 8, Oxford University Press
Cited by
Sorted by citations
The skin: an indispensable barrier
Proksch, E., Brandner, J. M., & Jensen, J. (2008) · Experimental Dermatology · doi:10.1111/j.1600-0625.2008.00786.x · Cited by 2,054 · see citing works
The cell-cell adhesion molecule E-cadherin
Roy, F. M. V., & Berx, G. (2008) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-008-8281-1 · Cited by 1,330 · see citing works
Cadherins and cancer: how does cadherin dysfunction promote tumor progression?
Jeanes, A., Gottardi, C. J., & Yap, A. S. (2008) · Oncogene · doi:10.1038/onc.2008.343 · Cited by 764 · see citing works
“Whereas acutely perturbing E-cadherin can prevent cells from effectively establishing a polarized phenotype, steady-state depletion of E-cadherin often does not overtly affect maintenance of polarity (Tunggal et al., 2005; Capaldo and Macara, 2007).”
E-cadherin, β-catenin, and ZEB1 in malignant progression of cancer
Schmalhofer, O., Brabletz, S., & Brabletz, T. (2009) · Cancer and Metastasis Reviews · doi:10.1007/s10555-008-9179-y · Cited by 766 · see citing works
“basal cell polarity and formation of tight junctions [36].”
BackgroundTight junctions/adherens junctions: basic structure and function
Niessen, C. M. (2007) · Journal of Investigative Dermatology · doi:10.1038/sj.jid.5700865 · Cited by 756 · see citing works
“This was associated with inappropriate localization of polarity proteins like aPKC, which is localized not only at tight junctions but at cell–cell contacts in all viable epidermal layers (Tunggal et al ., 2005).”
BackgroundSelf-citationInvolvement of Members of the Cadherin Superfamily in CancerPreprint
Berx, G., & Roy, F. M. V. (2009) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a003129 · Cited by 711 · see citing works
“In contrast, in mouse models specific loss of E-cadherin in the skin and the mammary gland is not sufficient for tumorigenesis (Boussadia et al. 2002; Tinkle et al. 2004; Tunggal et al. 2005).”
BackgroundDerksen, P. W. B., Liu, X., Saridin, F., van der Gulden, H., Zevenhoven, J., Evers, B., van Beijnum, J. R., Griffioen, A. W., Vink, J., Krimpenfort, P., et al. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.09.013 · Cited by 591 · see citing works
“These findings are consistent with previous work showing that conditional inactivation of E-cadherin in either skin or mammary epithelium does not induce tumor formation (Boussadia et al., 2002; Young et al., 2003; Tinkle et al., 2004; Tunggal et al., 2005).”
ResultDeconstructing the skin: cytoarchitectural determinants of epidermal morphogenesis
Simpson, C. L., Patel, D. M., & Green, K. J. (2011) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3175 · Cited by 516 · see citing works
“Epidermal adherens junctions are composed of the classic cadherins — E-cadherin and placental cadherin (P-cadherin; also known as cadherin 3) — both of which are important for skin morphogenesis: targeted ablation of E-cadherin causes hyperproliferation, defective differentiation and impaired barrier formation with lo…”
BackgroundEpidermal barrier formation and recovery in skin disorders
Segre, J. A. (2006) · Journal of Clinical Investigation · doi:10.1172/jci28521 · Cited by 508 · see citing works
Cell–Cell Junctions Organize Structural and Signaling NetworksPreprint
García, M. Á., Nelson, W. J., & Chavez, N. (2017) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a029181 · Cited by 506 · see citing works
“…in the epidermis of mice resulted in thickening of the epidermis and defects in terminal differen-tiationaswellasperinataldeathduetoimproper tight junction formation (Tinkle et al. 2004; Tunggal et al. 2005); hyperplasia also developed in aging keratinocytes derived from E-cadherin-knockout mice.”
BackgroundNiessen, C. M., Leckband, D., & Yap, A. S. (2011) · Physiological Reviews · doi:10.1152/physrev.00004.2010 · Cited by 427 · see citing works
“Thus conditional disruption of E-cadherin in the mouse skin was associated with mild adhesion defects (370, 423) or defective tight junctions (379), but did not disrupt epidermal integrity.”
BackgroundSelf-citationVandenesch, F., Lina, G., & Henry, T. (2012) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2012.00012 · Cited by 405 · see citing works
Aghapour, M., Raee, P., Moghaddam, S. J., Hiemstra, P. S., & Heijink, I. H. (2017) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2017-0200tr · Cited by 399 · see citing works
“In line with this, inhibition of PKD3 at baseline has been shown to enhance electrical resistance of airway epithelial cells in vitro, possibly via upregulation of CLDN1 (153).”
Deli, M. A. (2008) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2008.09.016 · Cited by 385 · see citing works
“Loss of E-cadherin in the epidermis, by conditionally inactivating its gene in mice, results in perinatal death due to the inability to retain a functional epidermal water barrier [47].”
BackgroundEpithelial cell dysfunction, a major driver of asthma development
Heijink, I. H., Kuchibhotla, V. N. S., Roffel, M. P., Maes, T., Knight, D. A., Sayers, I., & Nawijn, M. C. (2020) · Allergy · doi:10.1111/all.14421 · Cited by 331 · see citing works
Mechanisms Regulating Epithelial Stratification
Koster, M. I., & Roop, D. R. (2007) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.23.090506.123357 · Cited by 324 · see citing works
Calcium regulation of keratinocyte differentiation
Bikle, D. D., Xie, Z., & Tu, C. (2012) · Expert Review of Endocrinology & Metabolism · doi:10.1586/eem.12.34 · Cited by 327 · see citing works
Jantsch, J., Schatz, V., Friedrich, D., Schröder, A., Kopp, C., Siegert, I., Maronna, A., Wendelborn, D., Linz, P. R., Binger, K. J., et al. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.02.003 · Cited by 316 · see citing works
“The skin epidermis harbors a liquid-liquid interphase,where tight- junctions compartmentalize the extracellular fluid space and pre- vent transepidermal water losses (Furuse et al., 2002; Tunggal et al., 2005).”
BackgroundSherrill, J. D., KC, K., Wu, D. X.-Y., Djukic, Z., Caldwell, J. M., Stucke, E. M., Kemme, K. A., Costello, M. S., Mingler, M. K., Blanchard, C., et al. (2013) · Mucosal Immunology · doi:10.1038/mi.2013.90 · Cited by 314 · see citing works
Miroshnikova, Y. A., Le, H. Q., Schneider, D., Thalheim, T., Rübsam, M., Bremicker, N., Polleux, J., Kamprad, N., Tarantola, M., Wang, I., et al. (2017) · Nature Cell Biology · doi:10.1038/s41556-017-0005-z · Cited by 296 · see citing works
Self-citationIntercellular Junction Assembly, Dynamics, and HomeostasisPreprint
Green, K. J., Getsios, S., Troyanovsky, S. M., & Godsel, L. M. (2009) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a000125 · Cited by 259 · see citing works
“Although depletion of classical cadherins interferes with epidermal cohesion and the tight junction barrier in vivo, desmosomes still form in epidermis lacking classical cadherins or alpha-catenin (Vasioukhin et al. 2001a; Tunggal et al. 2005; Tinkle et al. 2008).”
BackgroundCapaldo, C., & Macara, I. G. (2006) · Molecular Biology of the Cell · doi:10.1091/mbc.e06-05-0471 · Cited by 258 · see citing works
“Postnatal lethality in mice with a conditional E-cadherin knockout in skin is due to failure of the epidermis to prevent water loss (Tinkle et al., 2004; Tunggal et al., 2005).”
BackgroundInfluentialMechanisms of cancer metastasis
Castañeda, M., den Hollander, P., Kuburich, N. A., Rosen, J. M., & Mani, S. A. (2022) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2022.10.006 · Cited by 253 · see citing works
The role of tight junctions in skin barrier function and dermal absorption
Bäsler, K., Bergmann, S., Heisig, M., Nägel, A., Zorn‐Kruppa, M., & Brandner, J. M. (2016) · Journal of Controlled Release · doi:10.1016/j.jconrel.2016.08.007 · Cited by 245 · see citing works
Cadherin-based intercellular adhesions organize epithelial cell–matrix traction forces
Mertz, A. F., Che, Y., Banerjee, S., Goldstein, J. M., Rosowski, K. A., Revilla, S. F., Niessen, C. M., Marchetti, M. C., Dufresne, E. R., & Horsley, V. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1217279110 · Cited by 243 · see citing works
“We further investigated the role of classical cadherins using primary keratinocytes from an epidermal-E-cadherin–knockout (KO) mouse (46).”
BackgroundSelf-citationBreitkreutz, D., Koxholt, I., Thiemann, K., & Nischt, R. (2013) · BioMed Research International · doi:10.1155/2013/179784 · Cited by 241 · see citing works
Mertens, A. E. E., Rygiel, T. P., Olivo, C., van der Kammen, R., & Collard, J. G. (2005) · The Journal of Cell Biology · doi:10.1083/jcb.200502129 · Cited by 238 · see citing works
“These conclusions are consistent with studies that show the activity of Cdc42 is dispensable for cell polarization in epithelial MDCK cells and epidermal keratinocytes (Gao et al., 2002; Tunggal et al., 2005), although another study has implicated Cdc42 in TJ biogenesis (Fukuhara et al., 2003).”
ResultBattle, M. A., Konopka, G., Parviz, F., Gaggl, A. L., Yang, C., Sladek, F. M., & Duncan, S. A. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0600246103 · Cited by 246 · see citing works
Airway epithelial regulation of pulmonary immune homeostasis and inflammation
Hallstrand, T. S., Hackett, T., Altemeier, W. A., Matute‐Bello, G., Hansbro, P. M., & Knight, D. A. (2013) · Clinical Immunology · doi:10.1016/j.clim.2013.12.003 · Cited by 223 · see citing works
“E-cadherin provides the architectural support required to form other junctional complexes, as delocalization of the TJ proteins ZO-1, occludin and claudins occurs following distorted AJ architecture [1,2].”
BackgroundEpidermal tight junctions in health and disease
Brandner, J., Zorn‐Kruppa, M., Yoshida, T., Moll, I., Beck, L. A., & Benedetto, A. D. (2014) · Tissue Barriers · doi:10.4161/21688370.2014.974451 · Cited by 221 · see citing works
“When applying this tracer to the dermis its movement out is limited by TJs, while it is largely restricted by the SC when applied on the skin surface.(3,11,15,16,21,29,37) This suggests that epidermal barrier function is quite complex, and the relative importance of the 2 major barrier structures (SC and TJ) may be in…”
BackgroundE-cadherin: gatekeeper of airway mucosa and allergic sensitization
Nawijn, M. C., Hackett, T., Postma, D. S., van Oosterhout, A. J. M., & Heijink, I. H. (2011) · Trends in Immunology · doi:10.1016/j.it.2011.03.004 · Cited by 218 · see citing works
Cadherins in development and cancer
Stemmler, M. P. (2008) · Molecular BioSystems · doi:10.1039/b719215k · Cited by 215 · see citing works
Tay, C. Y., Setyawati, M. I., Xie, J., Parak, W. J., & Leong, D. T. (2014) · Advanced Functional Materials · doi:10.1002/adfm.201401664 · Cited by 214 · see citing works
Caspase-8 deficiency in epidermal keratinocytes triggers an inflammatory skin disease
Kovalenko, A., Kim, J., Kang, T., Rajput, A., Bogdanov, K., Dittrich‐Breiholz, O., Kracht, M., Brenner, O. J., & Wallach, D. (2009) · The Journal of Experimental Medicine · doi:10.1084/jem.20090616 · Cited by 212 · see citing works
“JEM VOL. 206, September 28, 2009 ARTICLE 2165 function in vivo (Tunggal et al., 2005).”
BackgroundLoss of E-Cadherin-Dependent Cell–Cell Adhesion and the Development and Progression of CancerPreprint
Bruner, H. C., & Derksen, P. W. B. (2017) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a029330 · Cited by 213 · see citing works
“This is of interest because E-cadherin inactivation in postnatal skin is tolerated because of Pcadherin redundancy (Tinkle et al. 2004; Tunggal et al. 2005), implying a tissue-specific and context-dependent role for E-cadherin in the mammary gland.”
BackgroundRübsam, M., Mertz, A. F., Kubo, A., Marg, S., Jüngst, C., Goranci-Buzhala, G., Schauss, A. C., Horsley, V., Dufresne, E. R., Moser, M., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-01170-7 · Cited by 210 · see citing works
Self-citationA Key Role for E-cadherin in Intestinal Homeostasis and Paneth Cell Maturation
Schneider, M. R., Dahlhoff, M., Horst, D. A., Hirschi, B., Trülzsch, K., Müller‐Höcker, J., Vogelmann, R., Allgäuer, M., Gerhard, M., Steininger, S., et al. (2010) · PLoS ONE · doi:10.1371/journal.pone.0014325 · Cited by 206 · see citing works
“Here, loss of E-cadherin resulted in death of mice shortly after birth due to dehydration [41], altered differentiation [39], and disturbed epidermal integrity [40].”
BackgroundCoherent angular motion in the establishment of multicellular architecture of glandular tissues
Tanner, K., Mori, H., Mroue, R. M., Bruni‐Cardoso, A., & Bissell, M. J. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1119578109 · Cited by 204 · see citing works
12R-lipoxygenase deficiency disrupts epidermal barrier function
Epp, N., Fürstenberger, G., Müller, K., de Juanes, S., Leitges, M., Haußer, I., Thieme, F., Liebisch, G., Schmitz, G., & Krieg, P. (2007) · The Journal of Cell Biology · doi:10.1083/jcb.200612116 · Cited by 194 · see citing works
“…mouse models with epidermal barrier defects, including mice defi cient in KLF4 (Segre et al., 1999), claudin (Furuse et al., 2002), E-cadherin (Tunggal et al., 2005), LEKTI (Descargues et al., 2005), CAP1 (Leyvraz et al., 2005), and FATP4 (Herrmann et al., 2003), exhibited substantially less…”
BackgroundMethodInfluentialden Bossche, J. V., MALISSEN, B., Mantovani, A., BAETSELIER, P. D., & Ginderachter, J. A. V. (2011) · Blood · doi:10.1182/blood-2011-10-384289 · Cited by 183 · see citing works
“40-42 Next, PtdIns(3,4,5)P3 production in these nascent Ecadherin contacts triggers the recruitment of proteins containing pleckstrin homology domains, including Akt.”
BackgroundThe TRPV4 Channel Contributes to Intercellular Junction Formation in Keratinocytes
Sokabe, T., Fukumi-Tominaga, T., Yonemura, S., Mizuno, A., & Tominaga, M. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.103606 · Cited by 198 · see citing works
Gladden, A. B., Hebert, A. M., Schneeberger, E. E., & McClatchey, A. I. (2010) · Developmental Cell · doi:10.1016/j.devcel.2010.10.008 · Cited by 168 · see citing works
“Indeed, the polarity proteins Par3 and aPKC localize to the apical junction and are necessary both for the establishment of polarity and the formation of TJs (Goldstein and Macara, 2007; Helfrich et al., 2007; Suzuki et al., 2002; Suzuki and Ohno, 2006).”
BackgroundInfluentialKuo, I., Carpenter-Mendini, A. B., Yoshida, T., McGirt, L. Y., Ivanov, A. I., Barnes, K. C., Gallo, R. L., Borkowski, A. W., Yamasaki, K., Leung, D. Y. M., et al. (2012) · Journal of Investigative Dermatology · doi:10.1038/jid.2012.437 · Cited by 171 · see citing works
“…TJ components in cultured keratinocytes (Amagai et al., 2000; Baltes et al., 2004; Djalilian et al., 2006; Furuse et al., 2001; Furuse et al., 2002; Gareus et al., 2007; Kretz et al., 2004; Lucke et al., 1999; Ma et al., 2004; Ohnemus et al., 2008; Tunggal et al., 2005; Yuki et al., 2011a).”
BackgroundAdhesive and Signaling Functions of Cadherins and Catenins in Vertebrate DevelopmentPreprint
Stępniak-Konieczna, E., Radice, G. L., & Vasioukhin, V. I. (2009) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a002949 · Cited by 167 · see citing works
“Intriguingly, however, deletion of E-cadherin in embryonic skin epidermis did not result in a significant impairment of AJs, most likely because of compensatory up-regulation of P-cadherin (Young et al. 2003; Tinkle et al. 2004; Tunggal et al. 2005).”
BackgroundJensen, J., Pfeiffer, S., Witt, M., Bräutigam, M., Neumann, C., Weichenthal, M., Schwarz, T., Fölster‐Holst, R., & Proksch, E. (2009) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2009.07.015 · Cited by 165 · see citing works
Müller, E. J., Williamson, L., Kolly, C., & Suter, M. M. (2008) · Journal of Investigative Dermatology · doi:10.1038/sj.jid.5701248 · Cited by 161 · see citing works
“In support of a possible involvement of E-cadherin in growth control in keratinocytes in vivo, E-cadherinknockout epidermis displays some hyperproliferation, which however appears to be limited due to compensatory upregulation of P-cadherin (Young et al., 2003; Tinkle et al., 2004; Tunggal et al., 2005) or (as will be…”
BackgroundFunctions of EpCAM in physiological processes and diseases (Review)
Huang, L., Yang, Y., Yang, F., Liu, S., Zhu, Z., Lei, Z., & Guo, J. (2018) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2018.3764 · Cited by 162 · see citing works
“Notably, when E-cadherin is deleted from the mouse intestine, the barrier function of the intestines is compromised (38), moreover, loss of E-cadherin in mouse epidermis may lead to improper localization of the key tight junctional proteins, resulting in permeable TJs and altered epidermal resistance (39).”
BackgroundPan, T.-L., Wang, P.-W., Aljuffali, I. A., Huang, C.-T., Lee, C.-W., & Fang, J.-Y. (2015) · Journal of Dermatological Science · doi:10.1016/j.jdermsci.2015.01.011 · Cited by 158 · see citing works
Role of epithelial–mesenchymal transition in proliferative vitreoretinopathy
Tamiya, S., & Kaplan, H. J. (2015) · Experimental Eye Research · doi:10.1016/j.exer.2015.02.008 · Cited by 160 · see citing works
Heijink, I. H., Brandenburg, S. M., Noordhoek, J. A., et al. (2009) · European Respiratory Journal · doi:10.1183/09031936.00065809 · Cited by 156 · see citing works
Mechanical Forces in the Skin: Roles in Tissue Architecture, Stability, and Function
Biggs, L. C., Kim, C. S. K., Miroshnikova, Y. A., & Wickström, S. A. (2019) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2019.06.137 · Cited by 151 · see citing works
“These features highlight the unique, layer-specific distribution of tension within the epidermis and the role of this tension in barrier maintenance (Rübsam et al., 2017; Tunggal et al., 2005) (Figure 1).”
BackgroundLei, Z., Maeda, T., Tamura, A., Nakamura, T., Yamazaki, Y., Shiratori, H., Yashiro, K., Tsukita, S., & Hamada, H. (2012) · Developmental Biology · doi:10.1016/j.ydbio.2012.07.005 · Cited by 151 · see citing works
Rübsam, M., Broussard, J. A., Wickström, S. A., Nekrasova, O. E., Green, K. J., & Niessen, C. M. (2017) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a029207 · Cited by 148 · see citing works
“These TJs are essential to prevent unnecessary water loss from the organism (Furuse et al. 2002; Tunggal et al. 2005), an essential feature for terrestrial life.”
BackgroundSelf-citationWeber, S., Niessen, M. T., Prox, J., Lüllmann‐Rauch, R., Schmitz, A., Schwanbeck, R., Blobel, C., Jorissen, E., Strooper, B. D., Niessen, C. M., et al. (2011) · Development · doi:10.1242/dev.055210 · Cited by 150 · see citing works
“…signaling and Notch-dependent target genes (Lin and Kopan, 2003; Lin et al., 2000; Nicolas et al., 2003; Pan et al., 2004; Rangarajan et al., 2001; Uyttendaele et al., 2004; Yamamoto et al., 2003) have revealed a crucial role for Notch signaling in the proper stratification and development of the…”
Self-citationBarriers and more: functions of tight junction proteins in the skin
Kirschner, N., & Brandner, J. M. (2012) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2012.06554.x · Cited by 143 · see citing works
Desclozeaux, M., Venturato, J., Wylie, F. G., et al. (2008) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00097.2008 · Cited by 142 · see citing works
“E-cadherin is essential during development, from early embryogenesis through the later stages of organogenesis, as shown by genetic analysis in Drosophila and in knockdown mouse models (21, 38, 41).”
BackgroundChen, A., Beetham, H. G., Black, M. A., Priya, R., Telford, B. J., Guest, J., Wiggins, G. A. R., Godwin, T. D., Yap, A. S., & Guilford, P. (2014) · BMC Cancer · doi:10.1186/1471-2407-14-552 · Cited by 140 · see citing works
“Similarly, the targeted loss of E-cadherin from murine skin epithelium is also not associated with a significant loss of cell-cell adhesion, an effect attributed to compensatory upregulation of P-cadherin and desmosomal cadherin in the basal layer [32,33].”
BackgroundThe challenges of abundance: epithelial junctions and small GTPase signalling
Braga, V. M. M., & Yap, A. S. (2005) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2005.08.012 · Cited by 139 · see citing works
“Interestingly, inappropriate localization and activation of Rac in E-cadherin-null skin is also a potential cause of impairment in tight junction function and biogenesis [11 ].”
BackgroundTight junctions form a barrier in human epidermis
Kirschner, N., Houdek, P., Fromm, M., Moll, I., & Brandner, J. M. (2010) · European Journal of Cell Biology · doi:10.1016/j.ejcb.2010.07.010 · Cited by 139 · see citing works
Self-citationLoss of liver E-cadherin induces sclerosing cholangitis and promotes carcinogenesis
Nakagawa, H., Hikiba, Y., Hirata, Y., Font-Burgada, J., Sakamoto, K., Hayakawa, Y., Taniguchi, K., Umemura, A., Kinoshita, H., Sakitani, K., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1322731111 · Cited by 132 · see citing works
“Conditional knockout of E-cadherin in skin impairs an epidermal water-barrier function that leads to perinatal lethality (4).”
BackgroundMicroRNAs in skin and wound healing
Banerjee, J., Chan, Y. C., & Sen, C. K. (2010) · Physiological Genomics · doi:10.1152/physiolgenomics.00157.2010 · Cited by 138 · see citing works
New insights into cadherin function in epidermal sheet formation and maintenance of tissue integrity
Tinkle, C. L., Pasolli, H. A., Stokes, N., & Fuchs, E. V. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0807374105 · Cited by 134 · see citing works
“Interestingly, cadherin-deficient epidermis displayed defective localization of Par3, aPKC, and Scribble (Fig.”
BackgroundInfluentialYang, J.-X., Meyer, M., Müller, A.-K., Böhm, F., Grose, R., Dauwalder, T., Verrey, F., Kopf, M., Partanen, J., Bloch, W., et al. (2010) · Journal of Cell Biology · doi:10.1083/jcb.200910126 · Cited by 142 · see citing works
“Duplicate determinations were performed for each sample.”
Epithelial Cell Adhesion Molecule (EpCAM) Regulates Claudin Dynamics and Tight Junctions
Wu, C.-J., Mannan, P., Lu, M., et al. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.457499 · Cited by 132 · see citing works
“Adherens junctions are also required for TJ formation (32).”
BackgroundAirway epithelial barrier function regulates the pathogenesis of allergic asthma
Heijink, I. H., Nawijn, M. C., & Hackett, T. (2014) · Clinical & Experimental Allergy · doi:10.1111/cea.12296 · Cited by 126 · see citing works
Vocal Fold Epithelial Barrier in Health and Injury: A Research Review
Erickson, E., Leydon, C., & Thibeault, S. L. (2014) · Journal of Speech Language and Hearing Research · doi:10.1044/2014_jslhr-s-13-0283 · Cited by 128 · see citing works
Heijink, I. H., van Oosterhout, A. J. M., & Kapùs, A. (2010) · European Respiratory Journal · doi:10.1183/09031936.00125809 · Cited by 125 · see citing works
Derr, K., Zou, J., Luo, K., Song, M. J., Sittampalam, G. S., Zhou, C., Michael, S., Ferrer, M., & Derr, P. (2019) · Tissue Engineering Part C Methods · doi:10.1089/ten.tec.2018.0318 · Cited by 120 · see citing works
Kida, N., Sokabe, T., Kashio, M., Haruna, K., Mizuno, Y., Suga, Y., Nishikawa, K., Kanamaru, A., Hongo, M., Oba, A., et al. (2012) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-012-1081-3 · Cited by 121 · see citing works
“lacking E-cadherin, the main component of the AJ complex, specifically in the developing epidermis had a phenotype similar to the claudin-1-deficient mice [36].”
Kása, A., Csoŕtos, C., & Verin, A. D. (2014) · Tissue Barriers · doi:10.4161/21688370.2014.974448 · Cited by 119 · see citing works
“AJs assembly precedes tight junction formation and in some in vivo cases cadherin is required for the formation of TJs, as it controls the recruitment of ZO-1 to TJ complexes.(138) Up-regulation of ECspecific claudin-5 isoform is involved in EC barrier enhancement in some, but not all models.”
BackgroundLi, W., Chen, Z., Chin, I., Chen, Z., & Dai, H. (2018) · Current Neuropharmacology · doi:10.2174/1570159x16666180222164809 · Cited by 122 · see citing works
“The deletion of VE-cadherin in mice disrupted TJ integrity and altered localization of ZO-1, claudin-1, and claudin-4 by activating Rac and protein kinase C [61].”
BackgroundE-cadherin Beyond Structure: A Signaling Hub in Colon Homeostasis and Disease
Daulagala, A. C., Bridges, C., & Kourtidis, A. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20112756 · Cited by 119 · see citing works
“Importantly, E-cadherin is required for TJs and tissue barrier formation [20,21].”
BackgroundTight junction proteins in keratinocytes: localization and contribution to barrier function
Yuki, T., Haratake, A., Koishikawa, H., Morita, K., Miyachi, Y., & Inoue, S. (2007) · Experimental Dermatology · doi:10.1111/j.1600-0625.2006.00539.x · Cited by 117 · see citing works
Ciccocioppo, R., Finamore, A., Ara, C., Sabatino, A. D., Mengheri, E., & Corazza, G. R. (2006) · American Journal of Clinical Pathology · doi:10.1309/dtyr-a91g-8r0k-tm8m · Cited by 116 · see citing works
Ohnemus, U., Kohrmeyer, K., Houdek, P., Rohde, H., Wladykowski, E., Vidal, S., Horstkotte, M. A., Aepfelbacher, M., Kirschner, N., Behne, M. J., et al. (2008) · Journal of Investigative Dermatology · doi:10.1038/sj.jid.5701070 · Cited by 124 · see citing works
Role of aPKC Isoforms and Their Binding Partners Par3 and Par6 in Epidermal Barrier Formation
Helfrich, I., Schmitz, A., Zigrino, P., Michels, C., Haase, I., Bivic, A. L., Leitges, M., & Niessen, C. M. (2006) · Journal of Investigative Dermatology · doi:10.1038/sj.jid.5700621 · Cited by 112 · see citing works
“Interestingly, in the granular layer a highly concentrated staining was observed at lateral intercellular borders, which is reminiscent of the distribution of several tight junctional markers in the skin (Tunggal et al., 2005).”
BackgroundMethodResultInfluentialSelf-citationCell Adhesion in Epidermal Development and Barrier Formation
Sumigray, K., & Lechler, T. (2015) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/bs.ctdb.2014.11.027 · Cited by 110 · see citing works
“It is also becoming increasingly clear that not only does each cell–cell junction have its own independent functions, but also that there is crosstalk and interplay between the various junctional complexes that is important to give the epidermis full barrier activity (Godsel et al., 2010; Lewis et al., 1997; Sumigray,…”
BackgroundInfluentialSchamberger, A. C., Miše, N., Jia, J., Genoyer, E., Yildirim, A. Ö., Meiners, S., & Eickelberg, O. (2014) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2013-0090oc · Cited by 111 · see citing works
mTORC1 and mTORC2 regulate skin morphogenesis and epidermal barrier formation
Ding, X., Bloch, W., Iden, S., Rüegg, M. A., Hall, M. N., Leptin, M., Partridge, L., & Eming, S. A. (2016) · Nature Communications · doi:10.1038/ncomms13226 · Cited by 116 · see citing works
A rapidly prototyped lung-on-a-chip model using 3D-printed molds
Shrestha, J., Ghadiri, M., Shanmugavel, M., Bazaz, S. R., Vasilescu, S. A., Ding, L., & Warkiani, M. E. (2019) · Organs-on-a-Chip · doi:10.1016/j.ooc.2020.100001 · Cited by 111 · see citing works
Dynamics and Regulation of Epithelial Adherens Junctions
Ivanov, A. I., & Naydenov, N. G. (2013) · International review of cytology · doi:10.1016/b978-0-12-407697-6.00002-7 · Cited by 109 · see citing works
“Instead, it caused the increased paracellular permeability and hyperproliferation of keratinocytes (Tinkle et al., 2004; Tunggal et al., 2005).”
BackgroundAcharya, B. R., Wu, S. K., Lieu, Z. Z., Parton, R. G., Grill, S. W., Bershadsky, A. D., Gomez, G. A., & Yap, A. S. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.02.078 · Cited by 110 · see citing works
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“E-cadherin is essential for in vivo epidermal barrier function by regulating tight junctions.(20) Study of mechanistic underpinnings recognized cutaneous wound-edge miR-9 as being biofilminducible.”
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“E-cadherin is a major component of epidermal intercellular junctions, and its loss of expression correlates with impaired epidermal cell function and morphology 46 .”
Two-Path Impedance Spectroscopy for Measuring Paracellular and Transcellular Epithelial Resistance
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Self-citationTight junctions in skin inflammation
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Tight Junction Proteins Claudin-1 and Occludin Are Important for Cutaneous Wound Healing
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Dual role of E-cadherin in cancer cells
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E-cadherin is required for intestinal morphogenesis in the mouse
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“41,57-59 Surprisingly, our results ruled out a role for NM II in polyI:C-induced disassembly of apical junctions in our model's airway epithelial cells (1) because polyI:C did not trigger formation of contractile actomyosin structures, such as apical rings or vacuoles and (2) because pharmacologic inhibition of NM II…”
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Tight Junction Proteins in the Skin
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“Electron microscopy studies in claudin 6 transgenic mice have not yet been published.Epidermis-specific E-cadherin knockout mice demonstrate the interaction of AJ and TJ in the skin [”
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- Authors
- Tunggal, J. A., Helfrich, I., Schmitz, A., Schwarz, H., Günzel, D., Fromm, M., Kemler, R., Krieg, T., & Niessen, C. M.
- Affiliations
- University of Cologne (DE)
- Max Planck Institute for Developmental Biology (DE)
- Stiftung Charité (DE)
- Max Planck Society (DE)
- Corresponding author
- Niessen, Carien M
- Venue
- The EMBO Journal
- Published
- 2005-03-03
- Volume
- 24
- Issue
- 6
- Pages
- 1146-1156
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC556407
- OpenAlex
- W2145470537
- Semantic Scholar
- a188609a53de11c26fa2a5f349e10e9c4ff65cab
- Cited by
- 491
- References
- 53
- Citations by year
- 2026: 23 · 2025: 23 · 2024: 23 · 2023: 21 · 2022: 18 · 2021: 23 · 2020: 23 · 2019: 21 · 2018: 22 · 2017: 25 · 2016: 26 · 2015: 28 · 2014: 32 · 2013: 22 · 2012: 29
- FWCI
- 11.27
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Digital Library (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Northwestern University
- Deutsches Krebsforschungszentrum
- Deutsche Forschungsgemeinschaft (SFB589)
- Universität zu Köln
- University of North Carolina at Chapel Hill
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Skin and Cellular Biology Research
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Keywords
- E-cadherin, skin barrier function, tight junctions, desmosomes, stratified epithelium, conditional gene inactivation, epidermal permeability, Rac, atypical protein kinase C, perinatal lethality, cell adhesion
- MeSH terms
- Animals, Cell Communication, Desmosomes, Epidermis, Genes, Lethal, Membrane Proteins, Mice, Transgenic, Protein Kinase C, Water, Cadherins, Gene Deletion, Tight Junctions, rac GTP-Binding Proteins, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-27.
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