Abstract
Claudins are a large family of membrane proteins whose classic function is to regulate the permeability of tight junctions in epithelia. They are tetraspanins, with four alpha-helices crossing the membrane, two extracellular loops, a short cytoplasmic N-terminus and a longer and more variable C-terminus. The extracellular ends of the helices are known to undergo side-to-side (cis) interactions that allow the formation of claudin polymers in the plane of the membrane. The extracellular loops also engage in head-to-head (trans) interactions thought to mediate the formation of tight junctions. However, claudins are also present in intracellular structures, thought to be vesicles, with less well-characterized functions. Here, we briefly review our current understanding of claudin structure and function followed by an examination of changes in claudin mRNA and protein expression and localization through mammary gland development. Claudins-1, 3, 4, 7, and 8 are the five most prominent members of the claudin family in the mouse mammary gland, with varied abundance and intracellular localization during the different stages of post-pubertal development. Claudin-1 is clearly localized to tight junctions in mammary ducts in non-pregnant non-lactating animals. Cytoplasmic puncta that stain for claudin-7 are present throughout development. During pregnancy claudin-3 is localized both to the tight junction and basolaterally while claudin-4 is found only in sparse puncta. In the lactating mouse both claudin-3 and claudin-8 are localized at the tight junction where they may be important in forming the paracellular barrier. At involution and under challenge by lipopolysaccharide claudins −1, −3, and −4 are significantly upregulated. Claudin-3 is still colocalized with tight junction molecules but is also distributed through the cytoplasm as is claudin-4. These largely descriptive data provide the essential framework for future mechanistic studies of the function and regulation of mammary epithelial cell claudins.
Highlights
The claudin family comprises a large class of transmembrane proteins whose activity was first described in 1998 by Tsukita and colleagues who showed that claudin-1 and claudin-2 are important participants in tight junctions [1], interacting between cells to form the apical barrier that controls epithelial permeability (Fig. 1a)
In the non-pregnant non-lactating gland, both in virgin animals and after completion of involution, claudin-1 was the major claudin located in the tight junctions of the ductal cells
Claudins-3 and -7 were localized to numerous cytoplasmic puncta; claudin-4 was present as sparse puncta
Summary
The claudin family comprises a large class of transmembrane proteins whose activity was first described in 1998 by Tsukita and colleagues who showed that claudin-1 and claudin-2 are important participants in tight junctions [1], interacting between cells to form the apical barrier that controls epithelial permeability (Fig. 1a). We have shown that treatment of cultured cells with the DFYNP peptide, mentioned above, decreases cell motility and increases apoptosis through the FAS-dependent extrinsic pathway [12, 17, 18] Another tetraspanin, occludin, is exclusively localized to the tight junction in normal epithelia, but its function is not entirely clear as occludin knockout mice survive with intact epithelial structures [19]. Category 2 proteins include Rab7a as well as cell adhesion molecules, CD44 antigen, CEA1, integrins β and α2 and cytoskeletal related proteins BAI1 and Marcks-related protein These findings lead to a second hypothesis that claudin-4 localized to cytoplasmic vesicles is involved in cell-cell and cell-matrix interactions, potentially placing claudins as integrators of both cell-extrinsic and cell-intrinsic signal transduction pathways. We provide a comprehensive review of claudin expression and localization during mammary development; work on interacting proteins remains for the future
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