Epithelial Polarity. Gerard Apodaca Luciana I. Gallo. Colloquium series on Building BloCks of the Cell: Cell structure and function

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1 Colloquium series on Building BloCks of the Cell: Cell structure and function Series Editor: Ivan Robert Nabi Epithelial Polarity Gerard Apodaca Luciana I. Gallo life sciences Morgan & Claypool life SCIEnCES

3 Epithelial Polarity

4 ii Colloquium Digital Library of Life Sciences This e-book is a copyrighted work in the Colloquium Digital Library an innovative collection of time saving references and tools for researchers and students who want to quickly get up to speed in a new area or fundamental biomedical/life sciences topic. Each PDF e-book in the collection is an in-depth overview of a fast-moving or fundamental area of research, authored by a prominent contributor to the field. We call these e-books Lectures because they are intended for a broad, diverse audience of life scientists, in the spirit of a plenary lecture delivered by a keynote speaker or visiting professor. Individual e-books are published as contributions to a particular thematic series, each covering a different subject area and managed by its own prestigious editor, who oversees topic and author selection as well as scientific review. Readers are invited to see highlights of fields other than their own, keep up with advances in various disciplines, and refresh their understanding of core concepts in cell & molecular biology. For the full list of published and forthcoming Lectures, please visit the Colloquium homepage: Access to the Colloquium Digital Library is available by institutional license. Please info@morganclaypool.com for more information. Morgan & Claypool Life Sciences is a signatory to the STM Permission Guidelines. All figures used with permission.

5 iii Colloquium Series on Building Blocks of the Cell: Cell Structure and Function Editor Ivan Robert Nabi, Professor, University of British Columbia, Department of Cellular and Physiological Sciences This Series is a comprehensive, in-depth review of the key elements of cell biology including 14 different categories, such as Organelles, Signaling, and Adhesion. All important elements and interactions of the cell will be covered, giving the reader a comprehensive, accessible, authoritative overview of cell biology. All authors are internationally renowned experts in their area. Published titles (for future titles please see the website,

6 Copyright 2013 by Morgan & Claypool Life Sciences All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means electronic, mechanical, photocopy, recording, or any other except for brief quotations in printed reviews, without the prior permission of the publisher. Epithelial Polarity Gerard Apodaca and Luciana I. Gallo ISBN: paperback ISBN: ebook DOI: /C00077ED1V01Y201303BBC002 A Publication in the COLLOQUIUM SERIES ON BUILDING BLOCKS OF THE CELL Lecture #2 Series Editor: Ivan Robert Nabi, University of British Columbia, Department of Cellular and Physiological Sciences Series ISSN Pending

7 Epithelial Polarity Gerard Apodaca and Luciana I. Gallo Departments of Medicine and Cell Biology University of Pittsburgh COLLOQUIUM SERIES ON BUILDING BLOCKS OF THE CELL #2

8 vi Abstract Epithelial cells exhibit an apical basolateral axis of polarity that is generated during embryogenesis, is maintained throughout adult life in the face of constant cell regeneration, and is perturbed in several epithelial-associated diseases. We examine the structural and functional organization of epithelial tissues, as well as the events critical for generating epithelial asymmetry including vectorial trafficking of proteins and lipids, association of signaling and polarity proteins with subdomains of the plasma membrane, and 3D orientation of epithelial cells in response to cell cell and cell matrix interactions. As a paradigm to understand how these three processes are coordinated in time and space, we explore apical lumen formation. We also examine the final steps in epithelial morphogenesis, including brush border morphogenesis and ciliogenesis. Finally, we provide examples of disease processes that result from defects in epithelial polarity including diabetes insipidus, microvillar inclusion disease, hereditary deafness, ciliopathies, and cancer. Key words epithelial cells, epithelial tissues, epithelial structure, polarity, apical-basolateral axis, apical lumen formation, epithelial morphogenesis, epithelial polarity defects, epithelial-associated diseases, epithelial cell culture, membrane trafficking pathways, sorting and transport of proteins and membranes

9 vii Contents 1. Introduction Epithelial Cell Organization and Asymmetry Organization and Structure of Epithelial Cells Plasma Membrane Asymmetry Apical Membrane Domain Lateral Membrane Domain The Basal Membrane Membrane Organelle and Cytoskeletal Asymmetry Generation and Maintenance of Epithelial Polarity Model Systems to Study Epithelial Polarity Vectorial Trafficking Pathways in Polarized Epithelial Cells Biosynthetic Pathways Endocytic Pathways The Machinery for Vectorial Sorting and Transport of Proteins Sorting of Basolateral Membrane Proteins Sorting of Apical Membrane Proteins Transport Mechanisms and Membrane Fusion Role of Polarity Complexes and Signaling Machinery in Epithelial Polarization Function of Cell Cell and Cell Matrix Interactions in Epithelial Polarization Biogenesis of Luminal and Basolateral Membrane Domains Lumen Formation Formation of the Basolateral Domain... 58

10 viii Epithelial Polarity 3.7 Completion of Epithelial Morphogenesis Brush Border Morphogenesis Ciliogenesis and Membrane Traffic Generation of Cellular Asymmetry during Development Diseases that Result from Defects in Epithelial Polarity Mutations that Affect Sorting and Trafficking of Membrane Proteins Mutations in the Polarized Sorting/Trafficking Machinery Defects in Junction-Associated Proteins Ciliopathies Cancer and Epithelial Polarity Acknowledgments References Author Biographies

11 1 c h a p t e r 1 Introduction Cellular polarity refers to asymmetry in the shape, molecular composition, or function of cells and their organelles. It is a hallmark of most, if not, all cell types and required for their function (Figure 1) (Mellman and Nelson, 2008). For example, migration of a fibroblast depends on the formation of a leading and trailing edge, and long-range communication by neurons requires axons, specialized cell extensions that transmit information from the neuronal cell body to other cells in the body. One of the most easily identified polarized cell types are found in epithelial tissues, which are comprised of continuous sheets of adherent epithelial cells that cover the body surfaces and cavities, form glands, and line the inner and outer surfaces of sac- and tube-shaped organs. Epithelial cells characteristically have an apical basolateral asymmetry or polarity that is marked by compositionally, functionally, and morphologically distinct membrane domains: an apical one that is contiguous with the external milieu or faces the body cavities, and a basolateral domain that abuts the underlying tissues (Figure 1). By separating the external environment from an internal one, epithelial cells can perform specialized functions including vectorial water, ion, and peptide transport. Furthermore, their location at the interface of the external and internal milieus makes them ideally suited to form barriers to water, ions, and pathogens, to carry out immune surveillance, and to perform sensory transduction. A characteristic of most epithelial cells is that they undergo constant renewal. For example, the epithelial cells that line the gut or form the epidermis (the outer layer of the skin) have relatively rapid turnover rates of days, while the turnover rate of the uroepithelium that lines the bladder is estimated to be ~3 6 months (Hicks, 1975; Jost, 1989). Thus, polarity must be established de novo at each cell generation and then maintained, in some cases, for months. Furthermore, during development, epithelial polarity is rapidly gained as epithelial cell populations are formed and in some cases lost as epithelial cells become migratory (Bryant and Mostov, 2008). How epithelial polarity establishment and maintenance is accomplished has been the focus of study since the 1970s when investigators used epithelial cells infected with viruses or transduced with viral proteins to establish the importance of vectorial membrane/protein traffic to epithelial polarization (Rodriguez-Boulan et al., 2005). This was followed by work in the 1980s and 1990s that demonstrated the importance of cell adhesion to polarity and led to the identification of

12 2 Epithelial Polarity FIGURE 1: Polarized cell types. Each cell type depicted forms polarized membrane domains. Epithelial cells have distinct apical and basolateral membrane domains, separated by a junctional complex. Migrating fibroblasts have a leading and trailing edges. The neuronal cell body (soma) and its associated dendrites have a distinct protein and lipid composition from the axonal process.

13 Introduction 3 determinants in proteins that specify apical and basolateral sorting and that identified the importance of regulatory proteins such as Rab GTPases and SNARE proteins in these processes (Rodriguez-Boulan et al., 2005). Parallel studies in Caenorhabditis elegans and Drosophila melanogaster, which was initiated in the 1980s, led to the identification of three polarity complexes (Crumbs, Par, and Scribble complexes), which are conserved across the animal kingdom and critical to cellular polarization (Tepass et al., 2001). In the last fifteen years or so, we have first insights into the cytoplasmic machinery that recognizes polarized sorting signals, we have seen the discovery of additional polarity complexes, and we have an increased understanding of the role that lipids and their metabolism play in generating epithelial asymmetry (Mellman and Nelson, 2008; Rodriguez- Boulan et al., 2005). Our current understanding is that epithelial polarity depends on utilization of conserved machineries, which recognize intrinsic sorting signals in proteins and promote vectorial plasma membrane delivery (Mellman and Nelson, 2008). Furthermore, signaling and polarity proteins differentially associate with the plasma membrane, reinforcing membrane asymmetry by recruiting incoming membrane traffic. Finally, cell cell and cell matrix interactions allow the epithelial cell to orient in 3D space. It is the coordinated interplay between these events that promote polarization and allows cellular polarity to dynamically respond to changes in the cellular environment during development and in the process of normal tissue function. Here we examine the membrane asymmetry and specialized structures that characterize epithelial cells. Next, we explore how epithelial polarity is maintained and achieved, studying both the pathways, molecular machinery and polarity complexes, that lead to this remarkable phenomenon. Finally, we provide an overview of what happens when polarity is disrupted and how this leads to diseases that affect epithelial organization and function.

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