MOLECULAR STRUCTURE AND FUNCTION OF THE TIGHT JUNCTION Dynamic Regulation of Epithelial Cell Fate and Barrier Function by Intercellular Junctions Stefan Koch and Asma Nusrat Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, GA In the intestine, a single layer of epithelial cells effectively separates potentially harmful luminal content from the underlying tissue. The importance of an intact mucosal layer is highlighted by pathological disorders of the gut such as inflammatory bowel disease, in which disruption of the epithelial barrier leads to severe inflammation of the submu- cosal tissue compartments. Epithelial barrier function is provided by tightly regulated intercellular junctions, which consist of a plethora of membrane-associated and trans- membrane proteins organized in discreet, spatially restricted complexes. Classically, these complexes are known to be dynamic seals for fluids and small molecules, as well as to provide mechanical strength by anchoring cell-cell contacts to the cytoskeleton. Rather than just acting as simple gates and adapters, however, junctional complexes themselves can relay extracellular stimuli to the epithelium and initiate cellular re- sponses such as differentiation and apoptosis. In this review, we will highlight recent studies by our group and others which discuss how junctional proteins can promote outside-to-inside signaling and modulate epithelial cell fate. Unraveling the complex crosstalk between epithelial cells and their intercellular junctions is essential to under- standing how epithelial barrier function is maintained in vivo and might provide new strategies for the treatment of inflammatory disorders of the intestine. Key words: epithelium; epithelial barrier; intercellular junctions; tight junctions; ad- herens junctions; desmosomes; inflammation; inflammatory bowel disease; IBD; cytokines The mammalian intestinal tract is a highly or- ganized organ comprising many different cell types and harbors countless commensal mi- crobes, which assist in breaking down and ab- sorbing nutrients and water. The interface be- tween tissue compartments and the outside world consists of a single layer of epithelial cells that undergoes perpetual self-renewal originat- ing from a limited pool of pluripotent stem cells situated at or near the bottom of intestinal crypts (reviewed in Ref. 1). In an amazing dis- play of coordination, newly formed epithelial cells migrate from the bottom of the crypt to Address for correspondence: Asma Nusrat, 615 Michael Street, Atlanta, GA 30322. Voice: +404-727-8543; fax: +404-727-8538. anusrat@emory.edu the luminal surface, where they are shed into the intestinal lumen in a controlled fashion. During this whole process, the cells need to maintain the integrity of the epithelial barrier, as exposure of immune cells in the subepithe- lial tissue to luminal antigens would lead to a pronounced and harmful immune response. Indeed, a disruption of the intestinal barrier with resulting influx of bacteria and immune cells into the submucosa is a hallmark of in- flammatory bowel disease (IBD). IBD, which encompasses Crohn’s disease and ulcerative colitis, is a major idiopathic disorder in in- dustrialized countries. 2,3 A key mechanism in maintaining epithelial barrier function is the rapid regulated assembly and disassembly of intercellular junctions. Before we discuss how Molecular Structure and Function of the Tight Junction: Ann. N.Y. Acad. Sci. 1165: 220–227 (2009). doi: 10.1111/j.1749-6632.2009.04025.x c  2009 New York Academy of Sciences 220