From Cells to Organs: Building Polarized Tissue
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FOCUS ON CELL POLAREVIEWSRITY From cells to organs: building polarized tissue David M. Bryant* and Keith E. Mostov*‡ Abstract | How do animal cells assemble into tissues and organs? A diverse array of tissue structures and shapes can be formed by organizing groups of cells into different polarized arrangements and by coordinating their polarity in space and time. Conserved design principles underlying this diversity are emerging from studies of model organisms and tissues. We discuss how conserved polarity complexes, signalling networks, transcription factors, membrane-trafficking pathways, mechanisms for forming lumens in tubes and other hollow structures, and transitions between different types of polarity, such as between epithelial and mesenchymal cells, are used in similar and iterative manners to build all tissues. Basement membrane The defining feature of metazoa is that their cells ultimately, underlying blood vessels. The basal and A thin extracellular matrix layer are organized into multicellular tissues and organs. lateral surfaces are fairly similar in composition and that specifically lines the basal Although almost every eukaryotic cell is spatially organization and are often referred to together as side of epithelial sheets, and asymmetric or polarized, polarity must be coordi- the basolateral surface. The apical and basolateral certain other tissues, to which cells are attached. Also nated in space and time for individual cells to form surfaces, however, have very different compositions. 1 referred to as the basal lamina. a tissue . Cell polarity involves the asymmetric In vertebrates, tight junctions (TJs) are found at the organization of most of the physical aspects of the apical-most portion of the lateral surfaces, where Extracellular matrix cell, including the cell surface, intracellular organelles the TJs form barriers both between the apical and baso- An extracellular scaffolding gel and the cytoskeleton2,3. Analysis of the polarization lateral surfaces and between adjacent cells, limiting that consists of fibrous 7 structural proteins, complex of unicellular eukaryotes, such as yeast, has yielded paracellular permeability (FIG. 1a). sugars, fluid and signalling enormous insights into the mechanisms that underlie Many epithelial organs make use of interconnected molecules. the polarity of individual cells3. Formation of a tis- tubular networks, although the basic design principles sue, however, requires an ensemble cast; the emergent (as defined by Rafelski and Marshall8) are the same: a Tight junction A diffusion barrier-forming properties of the tissue result from the combined roles series of tubes terminates in a spherical ending or cap, junction at the apical-most of the individual cells that are involved. Accordingly, which is referred to as an acinus, end bud, alveolus or region of the lateral membrane several biological processes, including cell division, cyst in different tissues. Tubular networks can either of vertebrate epithelial cells. cell death, shape changes, cell migration and dif- arise independently and then become interconnected, ferentiation, must be coordinated with the polarity or can be branching trees that form via new sprouts Design principle 4 A simple rule that increases the requirements of a tissue to form an organ . from existing tubes. Many conserved morphogenetic likelihood of the proper Evolutionarily, epithelia are the most archetypal processes give rise to these structures, including mech- assembly and function of a polarized tissues in metazoa, with ~60% of mamma- anisms of lumen formation and expansion, tubulogen- system. lian cell types being of epithelial or epithelial-derived esis, branching morphogenesis, mesenchymal–epithelial origin5. Accordingly, the best studied polarized tissue is transitions (MET) and epithelial–mesenchymal transitions the simple epithelium of the mammalian intestine and (EMT). kidney, the cells of which are columnar in shape (that is, Cellular specialization through polarization occurs they are taller than they are wide). The apical surfaces in almost all cell types. Neural synapses have specialized 9 Departments of *Anatomy of these cells provide the luminal interface and are sites for neurotransmitter release and uptake (FIG. 1b). and ‡Biochemistry and specialized to regulate the exchange of materials, such The apical membranes of photoreceptor epithelium Biophysics, University of as nutrients from the intestine. The lateral surfaces of undergo light-sensing activity, whereas the basal sur- California San Francisco, these cells contact adjacent cells and have specialized faces connect to underlying neurons (FIG. 1c). Migrating California 94143-2140, USA. 3,6 (FIG. 1a) e-mails: david.bryant@ucsf. junctions and cell–cell adhesion structures . cells, such as neutrophils or Dictyostelium discoideum edu; [email protected] The basal surfaces of these cells contact the underly- amoebae, exhibit asymmetric front–back polarity as doi:10.1038/nrm2523 ing basement membrane, extracellular matrix (ECM) and, they move towards attractive cues10 (BOX 1). With a core NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 9 | NOVEMBER 2008 | 887 REVIEWS a Tubular epithelium requirement for cellular asymmetry in biological func- Tight junction Lumen tion, understanding how cells polarize and coordinate this process to form a tissue is a central question. Although many biological processes contribute to the formation of an organ, we will focus on how cell polar- Golgi ity is controlled and contributes to morphogenesis in the context of whole tissues. We discuss the molecular control of tissue polarization in in vivo organs and in Adherens Nucleus Lumen junction in vitro organotypic models, including the establish- ment, transcriptional control and molecular regulation Desmosomes ECM of tissue polarization, control of polarity orientation, and regulation of polarity by ECM and Rho GTPase signal- Basement Integrins membrane ling. We emphasize the role of epithelial lumen and tube formation and expansion, as epithelial tissues have b Neural synapse provided many fundamental insights into how polarity is Nucleus Axon shaft coordinated at the cellular, tissue and organ level. Soma Forming polarized tissue Axon terminal The organization of cells into tissues involves the Pre-synaptic concerted integration of polarizing cues from various Post-synaptic zone Synapse zone interdependent biological processes. First, cells must Dendrite sense their environment, including where they are in relation to their neighbours. This can be mediated by direct interaction of cells with the ECM through Neurotransmitter various receptors, such as integrin, dystroglycan receptor and proteoglycan molecules11,12. Cells can sense and modify the chemical composition, assembly, stiff- ness and other mechanical properties of the ECM13,14. Cells can also communicate with other cells through an array of adhesion molecules, such as cadherins15, Synaptic and through the sensing of diffusible factors, such vesicle as morphogens, chemoattractants and chemorepel- lants16. These combined cues provide instructions Adhesion molecules that enable cells to orientate their polarity and begin to assemble into groups. Second, cells in a forming c Drosophila melanogaster tissue must coordinate the asymmetrical distribution ommatidium Rhabdomere terminal web of polarity complexes17 to establish and enforce the gen- eration of an axis of asymmetric organization (BOX 1). Rhabdomere Lumen Concurrently with this second step, the cytoskeleton (IRS) and membrane-trafficking systems organize asym- metrically 2. These basic steps allow individual cells Stalk Zonula membrane adherens to become asymmetrically polarized (see the reviews by Bornens and by Nelson and Mellman in this issue). Examples of polarized epithelial and migratory cell Nucleus polarity and of the formation of polarity complexes Figure 1 | Cell polarization in diverse tissue types. a | Epithelial tubes are comprised are presented in BOX 1. of tightly adhering cells that display strong apico–basal polarity. Lateral membranes An important design principle is that polarization possess desmosomes, adherens junctions and tight junctionsNature Re (TJs),views providing | Molecular cell–cell Cell Biolog y must be coordinated between all cells in a tissue. For adhesion and diffusion barriers. Basal membranes interact with underlying basement example, although the organization of polarity com- membrane and extracellular matrix (ECM). Apical membranes are specialized for plexes, the cytoskeleton, membrane-trafficking events absorption and secretion, such as for electrolytes, milk or O2. b | Neurons polarize to form and adhesive junctions must be asymmetric in a single a soma (cell body), an axon shaft, an axon terminal and dendrites. Neural synapses cell, the orientation and organization of this asymmetry contain adhesion molecules for stabilization of the interaction between cells. The must be coordinated between neighbouring cells. In synapse provides a specialized region for neurotransmission to occur, through polarized addition to apico–basal polarity, some behaviours, such targeting and uptake of neurotransmitters. c | The Drosophila melanogaster retina contains ommatidia made up of tubular neuroepithelia surrounding a central lumen (or as cell division and migration, can also be polarized in interrhabdomeral space (IRS)). Cells are not radially symmetric in the tube but an orthogonal axis; that is, in the plane of the tissue. nevertheless follow a