Cell polarity

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 as Wnt, Nodal, and Bone 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.[13][14]

In addition to defining asymmetric axes in the adult organism, cell polarity also regulates both individual and collective cell movements during embryonic development such as apical constriction, invagination, and epiboly. 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 polarized vesicle transport along cytoskeletal filaments to deliver transmembrane proteins from the golgi 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, atypical protein kinase C),[15][16] Crumbs complex (Crb, PALS, PATJ, Lin7), and Scribble complex (Scrib, Dlg, Lgl).[17] 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.[18] Together with a group of signaling molecules called Rho GTPases, these polarity complexes can regulate vesicle transport and also control the localization of cytoplasmic proteins primarily by regulating the phosphorylation of phospholipids called phosphoinositides. Phosphoinositides serve as docking sites for proteins at the cell membrane, and their state of phosphorylation determines which proteins can bind.[19]

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.[20]

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 by Alan Turing in his 1953 paper 'The chemical basis of morphogenesis.'[21] While Turing initially attempted to explain pattern formation in a multicellular system, similar mechanisms can also be applied to intracellular pattern formation.[22] 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 the C. 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, the C. elegans-specific ring-finger-containing protein PAR-2, and LGL-1 (called posterior PAR proteins) are present mostly in the cytoplasm.[23] 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).[24][25] Anterior and posterior PAR proteins then maintain polarity until cytokinesis by mutually excluding each other from their respective cell membrane areas.