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      Claudin Loss-of-Function Disrupts Tight Junctions and Impairs Amelogenesis

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          Abstract

          Claudins are a family of proteins that forms paracellular barriers and pores determining tight junctions (TJ) permeability. Claudin-16 and -19 are pore forming TJ proteins allowing calcium and magnesium reabsorption in the thick ascending limb of Henle's loop (TAL). Loss-of-function mutations in the encoding genes, initially identified to cause Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis (FHHNC), were recently shown to be also involved in Amelogenesis Imperfecta (AI). In addition, both claudins were expressed in the murine tooth germ and Claudin-16 knockout (KO) mice displayed abnormal enamel formation. Claudin-3, an ubiquitous claudin expressed in epithelia including kidney, acts as a barrier-forming tight junction protein. We determined that, similarly to claudin-16 and claudin-19, claudin-3 was expressed in the tooth germ, more precisely in the TJ located at the apical end of secretory ameloblasts. The observation of Claudin-3 KO teeth revealed enamel defects associated to impaired TJ structure at the secretory ends of ameloblasts and accumulation of matrix proteins in the forming enamel. Thus, claudin-3 protein loss-of-function disturbs amelogenesis similarly to claudin-16 loss-of-function, highlighting the importance of claudin proteins for the TJ structure. These findings unravel that loss-of-function of either pore or barrier-forming TJ proteins leads to enamel defects. Hence, the major structural function of claudin proteins appears essential for amelogenesis.

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          Claudin-3 acts as a sealing component of the tight junction for ions of either charge and uncharged solutes.

          The paracellular barrier of epithelia and endothelia is established by several tight junction proteins including claudin-3. Although claudin-3 is present in many epithelia including skin, lung, kidney, and intestine and in endothelia, its function is unresolved as yet. We therefore characterized claudin-3 by stable transfection of MDCK II kidney tubule cells with human claudin-3 cDNA. Two clone systems were analyzed, exhibiting high or low claudin-2 expression, respectively. Expression of other claudins was unchanged. Ultrastructurally, tight junction strands were changed toward uninterrupted and rounded meshwork loops. Functionally, the paracellular resistance of claudin-3-transfected monolayers was strongly elevated, causing an increase in transepithelial resistance compared to vector controls. Permeabilities for mono- and divalent cations and for anions were decreased. In the high-claudin-2 system, claudin-3 reduced claudin-2-induced cation selectivity, while in the low-claudin-2 system no charge preference was observed, the latter thus reflecting the "intrinsic" action of claudin-3. Furthermore, the passage of the paracellular tracers fluorescein (332Da) and FD-4 (4kDa) was decreased, whereas the permeability to water was not affected. We demonstrate that claudin-3 alters the tight junction meshwork and seals the paracellular pathway against the passage of small ions of either charge and uncharged solutes. Thus, in a kidney model epithelium, claudin-3 acts as a general barrier-forming protein. Copyright © 2010 Elsevier B.V. All rights reserved.
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            Claudin-16 and claudin-19 interact and form a cation-selective tight junction complex.

            Tight junctions (TJs) play a key role in mediating paracellular ion reabsorption in the kidney. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is an inherited disorder caused by mutations in the genes encoding the TJ proteins claudin-16 (CLDN16) and CLDN19; however, the mechanisms underlying the roles of these claudins in mediating paracellular ion reabsorption in the kidney are not understood. Here we showed that in pig kidney epithelial cells, CLDN19 functioned as a Cl(-) blocker, whereas CLDN16 functioned as a Na(+) channel. Mutant forms of CLDN19 that are associated with FHHNC were unable to block Cl(-) permeation. Coexpression of CLDN16 and CLDN19 generated cation selectivity of the TJ in a synergistic manner, and CLDN16 and CLDN19 were observed to interact using several criteria. In addition, disruption of this interaction by introduction of FHHNC-causing mutant forms of either CLDN16 or CLDN19 abolished their synergistic effect. Our data show that CLDN16 interacts with CLDN19 and that their association confers a TJ with cation selectivity, suggesting a mechanism for the role of mutant forms of CLDN16 and CLDN19 in the development of FHHNC.
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              Tight junctions in skin inflammation.

              Inflammation of the skin is found after various external stimuli, e.g., UV radiation, allergen uptake, microbial challenge, or contact with irritants, as well as due to intrinsic, not always well-defined, stimuli, e.g., in autoimmune responses. Often, it is also triggered by a combination of both. The specific processes, which mean the kind of cytokines and immune cells involved and the extent of the reaction, depend not only on the trigger but also on the predisposition of the individual. Tight junctions (TJs) in the skin have been shown to form a barrier in the granular cell layer of the epidermis. Furthermore, TJ proteins were found in several additional epidermal layers. Besides barrier function, TJ proteins have been shown to be involved in proliferation, differentiation, cell-cell adhesion, and apoptosis in keratinocytes. In inflamed skin, TJ proteins are often affected. We summarize here the impact of skin inflammation on TJs, e.g., in various forms of dermatitis including atopic dermatitis, in skin infection, and in UV-irradiated skin, and discuss the role of TJs in these inflammatory processes.
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                Author and article information

                Contributors
                Journal
                Front Physiol
                Front Physiol
                Front. Physiol.
                Frontiers in Physiology
                Frontiers Media S.A.
                1664-042X
                24 May 2017
                2017
                : 8
                : 326
                Affiliations
                [1] 1Laboratory Orofacial Pathologies, Imaging and Biotherapies, Dental School, Paris Descartes University, Sorbonne Paris Cité Paris, France
                [2] 2Shanghai Key Laboratory of Stomatology, Department of Oral and Cranio-maxillofacial Science, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine Shanghai, China
                [3] 3Department of Odontology, AP-HP, and Reference Center for Rare Dieases of the Metabolism of Calcium and Phosphorus, Nord Val de Seine Hospital (Bretonneau) Paris, France
                [4] 4Department of Pediatric Nephrology, Charité University School of Medicine Berlin, Germany
                [5] 5Cordeliers Research Center, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale UMRS 1138, Paris-Diderot, Pierre et Marie Curie and Paris Descartes Universities, ERL Paris, France
                Author notes

                Edited by: Alexandre Rezende Vieira, University of Pittsburgh, United States

                Reviewed by: Yuqiao Zhou, University of Pittsburgh, United States; Claudio Cantù, University of Zurich, Switzerland; Jan Hu, University of Michigan, United States

                *Correspondence: Claire Bardet claire.bardet@ 123456parisdescartes.fr

                This article was submitted to Craniofacial Biology and Dental Research, a section of the journal Frontiers in Physiology

                Article
                10.3389/fphys.2017.00326
                5442167
                28596736
                4a8240d1-b387-4016-99ad-43cd70e115d5
                Copyright © 2017 Bardet, Ribes, Wu, Diallo, Salmon, Breiderhoff, Houillier, Müller and Chaussain.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 27 March 2017
                : 05 May 2017
                Page count
                Figures: 1, Tables: 0, Equations: 0, References: 16, Pages: 4, Words: 2646
                Funding
                Funded by: Université Paris Descartes 10.13039/501100005413
                Funded by: Fondation pour la Recherche Médicale 10.13039/501100002915
                Award ID: FRM DGE20111123012
                Categories
                Physiology
                Perspective

                Anatomy & Physiology
                amelogenesis imperfecta,enamel,barrier-forming tight junction protein,pore-forming tight junction protein,claudins

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