Clin Genet 2010: 77: 314 – 325 Printed in Singapore. All rights reserved  2010 John Wiley & Sons A/S CLINICAL GENETICS doi: 10.1111/j.1399-0004.2010.01397.x Developmental Biology: Frontiers for Clinical Genetics Section Editor: Jacques L. Michaud, email: jacques.michaud@recherche-ste-justine.qc.ca Olivier Pourquié, email: pourquie@igbmc.fr Claudins: unlocking the code to tight junction function during embryogenesis and in disease Gupta IR, Ryan AK. Claudins: unlocking the code to tight junction function during embryogenesis and in disease. Clin Genet 2010: 77: 314–325.  John Wiley & Sons A/S, 2010 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. IR Gupta and AK Ryan Departments of Pediatrics and Human Genetics, McGill University, Montr ´ eal, Qu ´ ebec, Canada Key words: claudin – tight junction – embryogenesis – epithelial cells – paracellular transport Corresponding author: Aimee K. Ryan, Research Institute of the McGill University Health Centre, Room 415/2 Place Toulon, 4060 Ste. Catherine St. West, Montr ´ eal, Qu ´ ebec, Canada, H3Z 2Z3. Tel.: +1 514 412 4400x 22853; fax: +1 514 412 4478; e-mail: aimee.ryan@mcgill.ca Received 7 February 2010, revised and accepted for publication 8 February 2010 Epithelial and endothelial cell layers play both a structural role in maintaining biological compart- ments and a barrier function that keeps the external and internal environments separate. In the early 1960s, studies using electron microscopy revealed that three distinct intercellular junctions linked epithelial or endothelial cells to one another: the zonula occludens (the tight junction), the zonula adherens (the adherens junction) and the macula adherens (the desmosome) (1). The most apical of these are the tight junctions, which form tight seals between the adjacent cells obliterating the inter- cellular space (Fig. 1). Tight junctions consist of multiple strands that surround the cell and extend across the lipid bilayer to form an anastomosing network with tight junction strands of adjacent cells. Within a cell, tight junctions act as a fence, which blocks the movement of membrane pro- teins between the apical and basolateral surfaces, thereby maintaining the apical-basal polarity of the cell (2–5). Between adjacent cells, tight junction strands function as a gate, which regulates para- cellular movement of ions and small molecules between the apical and basolateral surfaces of the layer. The tight junction gate functions as a dynamic barrier between the external and internal environments that can be altered in response to environmental, physiological and pharmacological cues (6). During the past decade, the claudin com- ponent of tight junctions was shown to determine the size and ion specificity of individual tight junc- tions. In this review, we will examine the roles 314