From cells to organs: building polarized tissue

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.

Figure 1. Cell polarization in diverse tissue types

a | Epithelial tubes are comprised of tightly adhering cells that display strong apico–basal polarity. Lateral membranes possess desmosomes, adherens junctions and tight junctions (TJs), providing cell–cell adhesion and diffusion barriers. Basal membranes interact with underlying basement membrane and extracellular matrix (ECM). Apical membranes are specialized for absorption and secretion, such as for electrolytes, milk or O₂. b | Neurons polarize to form a soma (cell body), an axon shaft, an axon terminal and dendrites. Neural synapses contain adhesion molecules for stabilization of the interaction between cells. The synapse provides a specialized region for neurotransmission to occur, through polarized targeting and uptake of neurotransmitters. c | The Drosophila melanogaster retina contains ommatidia made up of tubular neuroepithelia surrounding a central lumen (or interrhabdomeral space (IRS)). Cells are not radially symmetric in the tube but nevertheless follow a defined, polarized pattern. They have typical epithelial junctions (zonula adherens at the most apico–lateral region in D. melanogaster) and a subapical actin-dense network (the rhabdomere terminal web), but their apical surfaces are specialized into two domains; the stalk membrane and the light-sensing rhabdomeres, which are specialized microvilli.

Figure 2. EMT and MET in tissue morphogenesis

a | Epithelial cells from tubes undergoing epithelial–mesenchymal transition (EMT) lose apico–basal polarity, downregulate cell–cell adhesion, change their cytoskeleton composition and invade into the extracellular matrix (ECM) at areas where the basement membrane has broken down. As cells adopt a mesenchymal state, they may also be polarized, displaying front–back polarization and Golgi orientation towards the leading edge (front) during migration,. Conversely, during mesenchymal–epithelial transition (MET), cells develop apico–basal polarity, express epithelial-specific proteins, form stable adhesions and generate luminal structures. b | Transforming growth factor-β (TGFβ) (and other morphogens) can induce EMT by inducing Snail and the ZEB family of transcription factors (which can also crosstalk). Snail and ZEB directly repress the expression of numerous proteins that are involved in epithelial polarization, including polarity complexes,, cell–cell junctions, the ECM and the cytoskeleton. Snail-1 can also alter membrane trafficking, such as by direct repression of RAB25 (REF. 32), a small GTPase that is involved in apical membrane trafficking (although, paradoxically, RAB25 is overexpressed in some tumour types131). The miR-200 family of microRNAs promotes epithelial polarity and can induce MET by inhibiting translation of ZEB1, thereby blocking induction of EMT,.

Figure 3. Cavitation, hollowing and membrane repulsion as lumen-forming mechanisms

a | During cavitation, groups of cells proliferate to form a cell mass. Apoptosis of non-extracellular matrix (ECM)-contacting inner cells results in lumen and polarized tube or cyst formation. Correct lumen formation requires the PAR and Scribble complexes, which modulate cell proliferation. Apoptosis requires BCL2-family members (BCL2 and BIM) and is inhibited by proliferation-inducing oncoproteins (ERBB2, cyclin D1 and HPV16 E7), causing luminal filling,,. b | During hollowing, polarity establishment and orientation requires laminin–β1-integrin to signal RAC1 (REFS 12,37), and is inhibited by RhoA–ROCK1 signalling. Intracellular vesicles (varying in size in different systems71) containing apical membrane components and endocytosis- and/or trans-Golgi-derived material are delivered to regions between cells,,. This delivery depends on PTEN-mediated segregation of phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P₂) to nascent apical regions, recruiting annexin-2 and, in turn, the CDC42–aPKC–PAR6 complex,. Once rudimentary lumens are formed (there may be multiple such lumens), tight junctions,,, pump proteins,, the Crumbs complex,, the exocyst (Sec10 (REF. 136)) and possibly ezrin, promote formation of a single, expanded lumen. c | During Drosophila melanogaster cardiac tube formation, two rows of myoendothelial cells line up along the midline. Membrane processes extend and join between cells on either side of the midline, first at the ventral-most and then at the dorsal-most regions between cells. Resultant junctions containing PAR3 (Bazooka (Baz)), DE-cadherin (Shotgun (Shg)), β-catenin (Armadillo (Arm)) and Ena allow an enclosed lumen. Slit signalling to Robo at lumen surfaces, apparently regulated by dystroglycan (Dg), prevents extended adhesive contacts between cells (membrane repulsion), allowing lumens to form,.

Figure 4. Membrane traffic and apical extracellular matrix secretion during lumen formation and expansion

a | In the embryonic Drosophila melanogaster trachea an initially narrow lumen is expanded during a rapid burst of Molecular Cell Biology secretion at the apical membrane, dependent on the COPI and COPII vesicle transport complexes,. Chitin fibrils in the lumen (made by chitin synthetases) signal to underlying cells to organize luminal diameter before being subsequently remodelled into tracheal cuticle (reviewed in REF. 94). Clathrin-dependent endocytic activity at the apical surface directs luminal material to early endosomes (EE) and then to late endosomes (LE) for degradation, thereby clearing the lumen for gas entry. Correct luminal secretion and expansion requires functional septate junctions. b | Part of the D. melanogaster airway is divided into the dorsal trunk and dorsal branches, which sprout from the trunk. Wingless (Wg) signalling in the trunk induces the Spalt (SAL) transcription factor, which promotes DE-cadherin recycling through induction of the RIP11–RAB11 membrane-trafficking complex; lumens are formed by intercellular junctions between multiple cells. Decapentaplegic (Dpp) signalling in branches inhibits SAL expression, through the repressor Knirps (KNI), downregulating the RIP11–RAB11 complex and leading to formation of autocellular junctions and lumens in individual cells. c | During ommatidium formation in the D. melanogaster retina, a tripartite complex of RAB11, RIP11 and the motor protein myosin V (MyoV) regulates transport of cargo to the rhabdomere, and is required for correct ommatidia organization. RAB11 interacts with the exocyst complex, which also regulates apical transport to the rhabdomere. Luminal secretion of the proteoglycan eyes shut (EYS) is required for expansion of the interrhabdomeral space (IRS), apparently occurring in an exocyst-independent manner. ZA, zonula adherens.