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Cited by 1,512Barrier Structure and Function StudiesSkin and Cellular Biology ResearchAdvancements in Transdermal Drug Delivery

Claudin-based tight junctions are crucial for the mammalian epidermal barrier

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Furuse, Mikio, Hata, Masaki, Furuse, Kyoko, Yoshida, Yoko, Haratake, Akinori, Sugitani, Yoshinobu, Noda, Tetsuo, Kubo, Akiharu +1 more·2002·The Journal of Cell Biology
DOI 10.1083/jcb.200110122PMC PMC2173463
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Abstract

The tight junction (TJ) and its adhesion molecules, claudins, are responsible for the barrier function of simple epithelia, but TJs have not been thought to play an important role in the barrier function of mammalian stratified epithelia, including the epidermis. Here we generated claudin-1–deficient mice and found that the animals died within 1 d of birth with wrinkled skin. Dehydration assay and transepidermal water loss measurements revealed that in these mice the epidermal barrier was severely affected, although the layered organization of keratinocytes appeared to be normal. These unexpected findings prompted us to reexamine TJs in the epidermis of wild-type mice. Close inspection by immunofluorescence microscopy with an antioccludin monoclonal antibody, a TJ-specific marker, identified continuous TJs in the stratum granulosum, where claudin-1 and -4 were concentrated. The occurrence of TJs was also confirmed by ultrathin section EM. In claudin-1–deficient mice, claudin-1 appeared to have simply been removed from these TJs, leaving occludin-positive (and also claudin-4–positive) TJs. Interestingly, in the wild-type epidermis these occludin-positive TJs efficiently prevented the diffusion of subcutaneously injected tracer (∼600 D) toward the skin surface, whereas in the claudin-1–deficient epidermis the tracer appeared to pass through these TJs. These findings provide the first evidence that continuous claudin-based TJs occur in the epidermis and that these TJs are crucial for the barrier function of the mammalian skin.

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  • 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 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).”

    From E‐cadherin is essential for in vivo epidermal barrier function by regulating tight junctions (2005) · cites this paper as Furuse et al, 2002

    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)

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  • 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).”

    From E‐cadherin is essential for in vivo epidermal barrier function by regulating tight junctions (2005) · cites this paper as Furuse et al, 2002

  • 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).”

    From E‐cadherin is essential for in vivo epidermal barrier function by regulating tight junctions (2005) · cites this paper as Furuse et al, 2002

  • 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).”

    From E‐cadherin is essential for in vivo epidermal barrier function by regulating tight junctions (2005) · cites this paper as Furuse et al, 2002

  • Claudin-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).”

    From E‐cadherin is essential for in vivo epidermal barrier function by regulating tight junctions (2005) · cites this paper as Furuse et al, 2002

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Authors
Furuse, M., Hata, M., Furuse, K., Yoshida, Y., Haratake, A., Sugitani, Y., Noda, T., Kubo, A., & Tsukita, S.
Affiliations
  • Kyoto University (JP)
  • Kyoto Research Park (JP)
  • 4Basic Research Laboratory, Kanebo, Ltd., Kotobuki-cho, Odawara, Kanagawa 250-0002, Japan
  • Japanese Foundation For Cancer Research (JP)
  • Tohoku University (JP)
  • 1Department of Cell Biology, Kyoto University Faculty of Medicine, Yoshida-Konoe, Sakyo-ku, Kyoto 606-8501, Japan
ORCID
Venue
The Journal of Cell Biology
Publisher
Rockefeller University Press
Published
2002-03-11
Volume
156
Issue
6
Pages
1099-1111
ISSN
  • 0021-9525 (ISSN-L)
  • 1540-8140
DOI
10.1083/jcb.200110122
PMC
PMC2173463
OpenAlex
W2132024007
Cited by
1,512
References
1
Citations by year
2026: 38 · 2025: 53 · 2024: 54 · 2023: 59 · 2022: 67 · 2021: 63 · 2020: 77 · 2019: 76 · 2018: 61 · 2017: 79 · 2016: 77 · 2015: 67 · 2014: 77 · 2013: 80 · 2012: 77
FWCI
31.40
Type
journal article
Language
en
Open access
Locations
  • The Journal of Cell Biology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Funders
  • Deutsches Krebsforschungszentrum
  • Keio University
  • Japan Society for the Promotion of Science
Topics
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Skin and Cellular Biology Research
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advancements in Transdermal Drug Delivery
Keywords
tight junctions, claudin-1, claudin-4, occludin, skin barrier, skin barrier function, stratum granulosum, transepidermal water loss, keratinocytes, tight junction permeability, stratified epithelium
MeSH terms
Animals, Animals, Newborn, Cell Membrane Permeability, Epidermis, Female, Genes, Lethal, Graft Survival, Immunohistochemistry, Male, Membrane Proteins, Mice, Nude, Microscopy, Electron, Mutation, Keratinocytes, Skin Transplantation, Mice, Knockout, Tight Junctions, Mice, Claudin-1, Occludin

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