Trends in Cell Biology
Volume 16, Issue 4, April 2006, Pages 181-188
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Claudins in occluding junctions of humans and flies

https://doi.org/10.1016/j.tcb.2006.02.006Get rights and content

The epithelial barrier is fundamental to the physiology of most metazoan organ systems. Occluding junctions, including vertebrate tight junctions and invertebrate septate junctions, contribute to the epithelial barrier function by restricting free diffusion of solutes through the paracellular route. The recent identification and characterization of claudins, which are tight junction-associated adhesion molecules, gives insight into the molecular architecture of tight junctions and their barrier-forming mechanism in vertebrates. Mice lacking the expression of various claudins, and human hereditary diseases with claudin mutations, have revealed that the claudin-based barrier function of tight junctions is indispensable in vivo. Interestingly, claudin-like molecules have recently been identified in septate junctions of Drosophila. Here, we present an overview of recent progress in claudin studies conducted in mammals and flies.

Introduction

Distinct fluid compartments in the body and isolation from the external environment are crucial for the function of most organ systems in multicellular organisms. This compartmentalization is created by epithelia and endothelia, which not only selectively transport various substances through membrane pumps and channels, but also function as permeability barriers. Occluding junctions, including vertebrate tight junctions and various types of invertebrate septate junction, have important roles in establishing epithelial and endothelial barriers by regulating the paracellular flux of water-soluble molecules between adjacent cells. Tight junctions (TJs) are the most apical component of the junctional complex in vertebrates and are defined as focal contacts between the plasma membranes of adjacent cells in ultrathin section electron microscopy 1, 2. In the initial description by Farquhar and Palade, TJs were thought to be directly involved in the permeability barriers and were shown by electron microscopy to prevent the flux of proteins at the intercellular space [1]. Detailed physiological studies revealed that TJs contain aqueous pores that are permeable to small molecules, such as inorganic ions, with size and charge selectivity [2]. Importantly, the barrier characteristics (or permeability) of TJs vary considerably among different types of epithelium and endothelium depending on physiological requirements [3]. Clarification of the molecular properties of TJs has been a major challenge and evidence now shows that these can be explained by the properties of claudins, the major cell-adhesion molecules of TJs 4, 5, 6.

In general, invertebrate epithelial cells bear septate junctions (SJs) as the counterpart to vertebrate TJs and various SJ components have been identified [7]. Despite the morphological differences between TJs and SJs, recent genetic analyses of Drosophila have identified two claudin-like molecules at SJs that are involved in the paracellular permeability barrier 8, 9.

Here, we present an overview of recent advances in our understanding of the molecular structure and physiology of claudin-based TJs in vertebrates, and then discuss the claudin-like molecules that form invertebrate SJs.

Section snippets

Structure of TJ strands

When visualized using electron microscopy of ultrathin sections, TJs appear as a series of discrete sites of apparent fusion, involving the outer leaflets of the plasma membranes of adjacent cells. Using freeze fracture electron microscopy, TJs appear as a network of intramembranous particle strands (known as TJ strands) (Figure 1). These observations have led to our current understanding of the three-dimensional structure of TJs: each TJ strand associates laterally with another TJ strand in

Claudins in septate junctions of invertebrates

The regular occurrence of TJs in various epithelia is only observed in vertebrates and tunicates [7]. In invertebrates, SJs circumscribe epithelial cells and have been regarded as the functional counterparts of TJs [7] (Figure 1). SJs are characterized by a constant intercellular cleft of ∼15–20 nm, which is crossed by regularly spaced bridges called septa. Freeze-fracture replica electron microscopy was used to identify tightly spaced continuous or interrupted intramembrane parallel arrays of

Concluding remarks

Accumulated evidence in vertebrates reveals that claudins directly determine the barrier properties of the paracellular pathway. It is now widely accepted that the combination and mixing ratios of different claudin species determine the barrier properties of TJs depending on the tissues. More detailed understanding of the in vivo functions of claudins must await further studies of various claudin-deficient mice and human disorders caused by claudin mutations.

The most pressing challenge is to

Acknowledgements

We thank members of the Tsukita laboratory for helpful discussions. We are also very grateful to Masayuki Okada and Kyoko Furuse (KAN Research Institute, Inc.) for providing electron micrographs for Figure 1b-d.

An Editorial by Mikio Furuse on the life and work of Shoichiro Tsukita can be found in this issue of Trends in Cell Biology

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