Review
Paracellular barrier and channel functions of TJ claudins in organizing biological systems: Advances in the field of barriology revealed in knockout mice

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Abstract

Claudin was first identified as a four-transmembrane protein in the tight junctions (TJs) between epithelial cells. The claudin family has 27 members, which are specifically expressed depending on the epithelial cell type. Accumulating evidence has revealed that claudins are responsible for the paracellular barrier that prevents molecules from passing through epithelial cell sheets. In addition, the extracellular domains of some claudins enable them to act as a permselective paracellular channel for specific molecules, including ions and/or non-ionic solutes. Recent studies using claudin knockout mice revealed that the loss of claudins’ specific paracellular barrier and/or channel functions affects specific biological functions and leads to pathological states. In this review, considering recent findings in vivo, we describe how, sometimes in concert with canonical transporters and channels, the paracellular barrier and channel functions of claudins sophisticatedly organize biological systems.

Introduction

A multicellular organism enclosed by an epithelial cell sheet is separated into inner and outer parts [1]. The internal part of the body is further divided into many other compartments by sheets of epithelial cells (including endothelial and mesothelial cells), such as body cavities, intestinal lumens, blood vessels, nasal cavities, seminiferous tubules, thyroid gland follicles, and oviducts. Specific small and large compartments exist throughout the body; an organ is essentially a combination of epithelial cell sheet–lined compartments. The mechanism that prevents solutes from leaking between cells in the partition that separates the compartments is called the “paracellular barrier” [2], [3], [4]. On the other hand, the epithelial cell body itself serves as a barrier, the “transcellular barrier,” due to its plasma membrane. The homeostasis in each epithelial cell sheet-lined compartment is not static, but is dynamically maintained by the paracellular and transcellular barrier and the selective exchange of molecules across the epithelial cell sheet barrier (Fig. 1, Fig. 2, Fig. 3, Fig. 4).

Section snippets

Identification of claudins as the basic epithelial TJ proteins

Although the concept of tight junction (TJ)-based paracellular barrier has been developed after 1885 [5] primarily from the morphological and physiological aspects, the contribution of cell–cell adhesive membrane proteins to TJ formation was not established, until the TJ claudins were identified to play this role, in 1998, when it leads to the field of Barriology [6], [7], [8], [9], [10], [11].

Although the identity of the unique TJ transmembrane molecules was an intriguing mystery for many

Organ-dependent expressions of claudin family members

Organs include many types of epithelial cells, in which claudins exhibit distinct expression patterns. In most epithelia, more than three species of claudins are expressed, which vary in type and relative amount. At one extreme, only a few (1–3) claudin species are very dominantly expressed in a tissue and at the other, nearly all the claudins are expressed and produce an averaged effect. There are also various intermediate cases that lie between these two extreme ones [16], [18].

For example,

Characterization of claudins as paracellular barrier proteins, and as paracellular channel proteins in some cases

As described above, claudins were first characterized as TJ proteins because of their TJ localization [6], [7]. Although other membrane proteins, like occludin, tricellulin, JAM, and CAR have also been identified as TJ proteins, claudins are the most essential, because they form the TJ strands that create the paracellular barrier [8], [29], [30], [31]. Claudin is the only protein which can form steady strands in overexpressed fibroblasts which originally do not express claudin molecules.

When

Structure of TJ claudin

One of the most powerful approaches to studying the paracellular barrier and channel is the high-resolution crystallography of transmembrane proteins [39]. Recently, the crystal structure of claudin-15 was clarified to 2.4-Å resolution, which revealed a characteristic β-sheet fold comprised of two extracellular segments and five β-strands connected to a four-helix transmembrane motif [40]. The five β-sheets extend on the outer surface of the membrane, forming a palm-like configuration. The

TJ claudins as organizers of paracellular and intracellular events

The TJs also play important roles in intracellular events, such as those related to cytoskeletal networks, signaling pathways, and vesicle trafficking. In these processes, claudins are directly associated with scaffold proteins, such as ZO1/2 [8], [41]. Hence, TJs play crucial roles in paracellular and intracellular functions, and in their cooperative functions. However, we are focusing on the paracellular role of TJs in organizing biological systems in this review.

Paracellular roles of claudins in biological systems as revealed by knockout (KO) mouse studies

The paracellular barrier function of TJ claudins is probably the simplest to interpret experimentally, since their dysfunction leads to the diffusion of some molecules that are normally blocked, although the specificity of the barrier function for various kinds of molecules differs between claudins. The roles of specific claudins in organizing biological systems that respond to environmental cues, have begun to be revealed by in vivo analyses of KO mice. Compared to the paracellular barrier

Specific paracellular barrier functions of claudins in biological systems suggested by knockout (KO) mouse studies

Since claudins are the paracellular barrier proteins, the mechanism for barrier creation should be similar for all claudins; that is, they all closely attach to the two membranes of neighboring epithelial cells at their apical region. On the other hand, accumulating evidence indicates that different specific paracellular barrier functions occur under certain conditions, depending on the types of claudins involved. A paracellular barrier role has been suggested for claudins-1, -3, -4, -5, -11,

Specific paracellular channel functions of claudins in biological systems suggested by knockout (KO) mouse studies

A paracellular channel role has been suggested for claudins-2, -7, -10, -15, -16, -17 and in limited cases for claudin-4. KO mouse studies supporting this role have been performed for claudins-2, -7, -10, -15, and -16.

Conclusion and perspectives

The TJ paracellular barrier proteins are claudins, of which there are 27 family members. Some claudin family members form paracellular channels for select molecules, such as ions and non-ionic solutes. The paracellular barrier and channel functions of claudins are critical microenvironmental regulators in the body, and their roles should be systematically analyzed as “barriology” [7], [9]. The claudins determine the functional parameters of epithelial cell sheets, which not only enclose the

Acknowledgments

We thank all the members of our laboratory for helpful discussions. We thank Drs. H. Suziki, K. Tani, and Y. Fujiyoshi in Nagoya University for collaboration and discussion. Our program is supported by Grants-in-Aid for Scientific Research (A) and Creative Scientific Research from the Ministry of Education, Culture, and Sports, Science and Technology of Japan, and by CREST (Core Research for Evolutional Science and Technology) of Japan Science and Technology Agency to Sachiko Tsukita.

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