Cell polarity refers to spatial differences in shape, structure, and function within acell. Almost all cell types exhibit some form of polarity, which enables them to carry out specialized functions. Classical examples of polarized cells are described below, including epithelial cells with apical-basal polarity,neurons in which signals propagate in one direction fromdendrites toaxons, andmigrating cells. Furthermore, cell polarity is important during many types ofasymmetric cell division to set up functional asymmetries between daughter cells.
Many of the key molecular players implicated in cell polarity are well conserved. For example, inmetazoan cells, the PAR-3/PAR-6/aPKC complex plays a fundamental role in cell polarity. While the biochemical details may vary, some of the core principles such as negative and/or positive feedback between different molecules are common and essential to many known polarity systems.[1]
Epithelial cells adhere to one another throughtight junctions,desmosomes andadherens junctions, forming sheets of cells that line the surface of the animal body and internal cavities (e.g., digestive tract and circulatory system). These cells have an apical-basal polarity defined by theapical membrane facing the outside surface of the body, or thelumen of internal cavities, and thebasolateral membrane oriented away from the lumen. The basolateral membrane refers to both the lateral membrane where cell-cell junctions connect neighboring cells and to the basal membrane where cells are attached to thebasement membrane, a thin sheet ofextracellular matrix proteins that separates the epithelial sheet from underlying cells andconnective tissue. Epithelial cells also exhibitplanar cell polarity, in which specialized structures are orientated within the plane of the epithelial sheet. Some examples of planar cell polarity include the scales of fish being oriented in the same direction and similarly the feathers of birds, the fur of mammals, and the cuticular projections (sensory hairs, etc.) on the bodies and appendages of flies and other insects.[2] Computational models have been suggested to simulate how a group of epithelial cells can form a variety of biological morphologies.[3]
A neuron receives signals from neighboring cells through branched, cellular extensions calleddendrites. The neuron then propagates an electrical signal down a specializedaxon extension from the basal pole to the synapse, where neurotransmitters are released to propagate the signal to another neuron or effector cell (e.g., muscle or gland). The polarity of the neuron thus facilitates the directional flow of information, which is required for communication between neurons and effector cells.[4]
Many cell types are capable of migration, such asleukocytes andfibroblasts, and in order for these cells to move in one direction, they must have a defined front and rear. At the front of the cell is the leading edge, which is often defined by a flat ruffling of the cell membrane called thelamellipodium or thin protrusions calledfilopodia. Here,actin polymerization in the direction of migration allows cells to extend the leading edge of the cell and to attach to the surface.[5] At the rear of the cell, adhesions are disassembled and bundles of actinmicrofilaments, calledstress fibers, contract and pull the trailing edge forward to keep up with the rest of the cell. Without this front-rear polarity, cells would be unable to coordinate directed migration.[6][7][8]
The budding yeast,Saccharomyces cerevisiae, is a model system for eukaryotic biology in which many of the fundamental elements of polarity development have been elucidated. Yeast cells share many features of cell polarity with other organisms, but feature fewer protein components. In yeast, polarity is biased to form at an inherited landmark, a patch of the protein Rsr1 in the case of budding, or a patch of Rax1 in mating projections.[9] In the absence of polarity landmarks (i.e. in gene deletion mutants), cells can perform spontaneoussymmetry breaking,[10] in which the location of the polarity site is determined randomly. Spontaneous polarization still generates only a single bud site, which has been explained by positive feedback increasing polarity protein concentrations locally at the largest polarity patch while decreasing polarity proteins globally by depleting them. The master regulator of polarity in yeast isCdc42, which is a member of the eukaryotic Ras-homologousRho-family of GTPases, and a member of the super-family of small GTPases, which include Rop GTPases in plants and small GTPases in prokaryotes. For polarity sites to form, Cdc42 must be present and capable of cycling GTP, a process regulated by itsguanine nucleotide exchange factor (GEF), Cdc24, and by itsGTPase-activating proteins (GAPs). Cdc42 localization is further regulated by cell cycle queues, and a number of binding partners.[11] A recent study to elucidate the connection between cell cycle timing andCdc42 accumulation in the bud site usesoptogenetics to control protein localization using light.[12] During mating, these polarity sites can relocate. Mathematical modeling coupled with imaging experiments suggest the relocation is mediated by actin-driven vesicle delivery.[13][14]
The bodies of vertebrate animals are asymmetric along three axes:anterior-posterior (head to tail),dorsal-ventral (spine to belly), and left-right (for example, our heart is on the left side of our body). These polarities arise within the developing embryo through a combination of several processes: 1)asymmetric cell division, in which two daughter cells receive different amounts of cellular material (e.g. mRNA, proteins), 2) asymmetric localization of specific proteins or RNAs within cells (which is often mediated by the cytoskeleton), 3) concentration gradients of secreted proteins across the embryo such asWnt,Nodal, andBone Morphogenic Proteins (BMPs), and 4) differential expression of membrane receptors and ligands that cause lateral inhibition, in which the receptor-expressing cell adopts one fate and its neighbors another.[15][16]
In addition to defining asymmetric axes in the adult organism, cell polarity also regulates both individual and collective cell movements during embryonic development such asapical constriction,invagination, andepiboly. These movements are critical for shaping the embryo and creating the complex structures of the adult body.
Cell polarity arises primarily through the localization of specific proteins to specific areas of the cell membrane. This localization often requires both the recruitment of cytoplasmic proteins to the cell membrane and polarizedvesicle transport alongcytoskeletal filaments to deliver transmembrane proteins from thegolgi apparatus. Many of the molecules responsible for regulating cell polarity are conserved across cell types and throughout metazoan species. Examples include the PAR complex (Cdc42, PAR3/ASIP, PAR6, atypicalprotein kinase C),[17][18] Crumbs complex (Crb, PALS, PATJ, Lin7), and Scribble complex (Scrib, Dlg, Lgl).[19] These polarity complexes are localized at the cytoplasmic side of the cell membrane, asymmetrically within cells. For example, in epithelial cells the PAR and Crumbs complexes are localized along the apical membrane and the Scribble complex along the lateral membrane.[20] Together with a group of signaling molecules calledRho GTPases, these polarity complexes can regulate vesicle transport and also control the localization of cytoplasmic proteins primarily by regulating the phosphorylation of phospholipids calledphosphoinositides. Phosphoinositides serve as docking sites for proteins at the cell membrane, and their state of phosphorylation determines which proteins can bind.[21]
While many of the key polarity proteins are well conserved, different mechanisms exist to establish cell polarity in different cell types. Here, two main classes can be distinguished: (1) cells that are able to polarize spontaneously, and (2) cells that establish polarity based on intrinsic or environmental cues.[22]
Spontaneous symmetry breaking can be explained by amplification of stochastic fluctuations of molecules due to non-linear chemical kinetics. The mathematical basis for this biological phenomenon was established byAlan Turing in his 1953 paper 'The chemical basis of morphogenesis.'[23] While Turing initially attempted to explain pattern formation in a multicellular system, similar mechanisms can also be applied to intracellular pattern formation.[24] Briefly, if a network of at least two interacting chemicals (in this case, proteins) exhibits certain types of reaction kinetics, as well as differential diffusion, stochastic concentration fluctuations can give rise to the formation of large-scale stable patterns, thus bridging from a molecular length scale to a cellular or even tissue scale.
A prime example for the second type of polarity establishment, which relies on extracellular or intracellular cues, is theC. elegans zygote. Here, mutual inhibition between two sets of proteins guides polarity establishment and maintenance. On the one hand, PAR-3, PAR-6 and aPKC (called anterior PAR proteins) occupy both the plasma membrane and cytoplasm prior to symmetry breaking. PAR-1, theC. elegans-specific ring-finger-containing protein PAR-2, and LGL-1 (called posterior PAR proteins) are present mostly in the cytoplasm.[25] The male centrosome provides a cue, which breaks an initially homogenous membrane distribution of anterior PARs by inducing cortical flows. These are thought to advect anterior PARs towards one side of the cell, allowing posterior PARs to bind to other pole (posterior).[26][27] Anterior and posterior PAR proteins then maintain polarity until cytokinesis by mutually excluding each other from their respective cell membrane areas.
