Claudins: Unlocking the code to tight junction function during embryogenesis and in disease

Department of Pediatrics, McGill University, Montréal, Québec, Canada.
Clinical Genetics (Impact Factor: 3.93). 04/2010; 77(4):314-25. DOI: 10.1111/j.1399-0004.2010.01397.x
Source: PubMed


Gupta IR, Ryan AK. Claudins: unlocking the code to tight junction function during embryogenesis and in disease.
Claudins are the structural and molecular building blocks of tight junctions. Individual cells express more than one claudin family member, which suggests that a combinatorial claudin code that imparts flexibility and dynamic regulation of tight junction function could exist. Although we have learned much from manipulating claudin expression and function in cell lines, loss-of-function and gain-of-function experiments in animal model systems are essential for understanding how claudin-based boundaries function in the context of a living embryo and/or tissue. These in vivo manipulations have pointed to roles for claudins in maintaining the epithelial integrity of cell layers, establishing micro-environments and contributing to the overall shape of an embryo or tissue. In addition, loss-of-function mutations in combination with the characterization of mutations in human disease have demonstrated the importance of claudins in regulating paracellular transport of solutes and water during normal physiological states. In this review, we will discuss specific examples of in vivo studies that illustrate the function of claudin family members during development and in disease.

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    • "Apparently , lineage - specific ex - pansion of claudin genes is also involved in the genomes of teleost after the whole genome duplication event , as supported by the presence of claudin genes that are clustered on a single chromosome . Claudins are involved in responses to pathogen infection and hypox - ia stress ( Findley and Koval , 2009 ; Guttman and Finlay , 2009 ; Gupta and Ryan , 2010 ; Soini , 2011 ; Zhang et al . , 2012 ; Kolosov et al . "
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    ABSTRACT: Claudins are one of the major groups of transmembrane proteins that play crucial roles in tight junctions. In addition to their function in regulation of paracellular permeability, claudins are also involved in a number of biological processes related to pathogen infection, embryonic development, organ development and hypoxia response. Despite its importance, analyses of claudin genes in channel catfish have not been systematically performed. In this study, a total of 52 claudin genes were identified and characterized in channel catfish. Phylogenetic analyses were conducted to determine their identities and identify a number of lineage-specific claudin gene duplications in channel catfish. Expression profiles of catfish claudin genes in response to enteric septicemia of catfish (ESC) disease and hypoxia stress were determined by analyzing existing RNA-Seq datasets. Claudin genes were significantly down-regulated in the intestine at 3 h post-infection, indicating that pathogens may disrupt the mucosal barrier by suppressing the expression of claudin genes. A total of six claudin genes were significantly regulated in the gill after hypoxia stress. Among them, the expression of cldn-11b and cldn-10d were dramatically altered when comparing hypoxia tolerant fish with intolerant fish, though their specific roles involved in response to hypoxia stress remained unknown.
    Comparative Biochemistry and Physiology Part D Genomics and Proteomics 01/2015; 13C. DOI:10.1016/j.cbd.2015.01.002 · 2.06 Impact Factor
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    • "They form a tight seal between adjacent cells that restricts paracellular transport (gate function) and separates the apical and basolateral domains of the plasma membrane to maintain cell polarity (fence function). These dynamic structures respond to a variety of environmental, physiological and pharmacological cues, and it is well accepted that their dysfunction or disruption, and the ensuing loss of tissue organization contribute to the development and progression of cancer [1–3]. The three principal components of tight junctions are occludin, claudins and junctional adhesion molecule (JAM), but only claudins are considered indispensable for tight junction formation [1–5]. "
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    ABSTRACT: Downregulation of the tight junction protein claudin 1 is a frequent event in breast cancer and is associated with recurrence, metastasis, and reduced survival, suggesting a tumor suppressor role for this protein. Tumor suppressor genes are often epigenetically silenced in cancer. Downregulation of claudin 1 via DNA promoter methylation may thus be an important determinant in breast cancer development and progression. To investigate if silencing of claudin 1 has an epigenetic etiology in breast cancer we compared gene expression and methylation data from 217 breast cancer samples and 40 matched normal samples available through the Cancer Genome Atlas (TCGA). Moreover, we analyzed claudin 1 expression and methylation in 26 breast cancer cell lines. We found that methylation of the claudin 1 promoter CpG island is relatively frequent in estrogen receptor positive (ER+) breast cancer and is associated with low claudin 1 expression. In contrast, the claudin 1 promoter was not methylated in most of the ER-breast cancers samples and some of these tumors overexpress claudin 1. In addition, we observed that the demethylating agents, azacitidine and decitabine can upregulate claudin 1 expression in breast cancer cell lines that have a methylated claudin 1 promoter. Taken together, our results indicate that DNA promoter methylation is causally associated with downregulation of claudin 1 in a subgroup of breast cancer that includes mostly ER+ tumors, and suggest that epigenetic therapy to restore claudin 1 expression might represent a viable therapeutic strategy in this subtype of breast cancer.
    PLoS ONE 07/2013; 8(7):e68630. DOI:10.1371/journal.pone.0068630 · 3.23 Impact Factor
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    • "In the ''cell adhesion'' related sub-network, mRNAs encoding claudins 2, 3, 7, 8, and 18 and tight junction protein 3 were decreased in Klf5 D/D intestines. Claudins are the structural and molecular building blocks of tight junctions involved in maintaining epithelial integrity, establishing micro-environments and contributing to the overall shape of tissues or cells (Gupta and Ryan, 2010). "
    Developmental Biology 03/2013; 375(2):128. · 3.55 Impact Factor
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