Epithelial polarity is one example of the

cell polarity Cell polarity refers to spatial differences in shape, structure, and function within a cell. Almost all cell types exhibit some form of polarity, which enables them to carry out specialized functions. Classical examples of polarized cells are desc ...

that is a fundamental feature of many types of

cell Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery ...

s. Epithelial cells feature distinct 'apical', 'lateral' and 'basal'

plasma membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...

domains. Epithelial cells connect to one another via their lateral membranes to form epithelial sheets that line cavities and surfaces throughout the animal body. Each plasma membrane domain has a distinct protein composition, giving them distinct properties and allowing directional transport of molecules across the epithelial sheet. How epithelial cells generate and maintain polarity remains unclear, but certain molecules have been found to play a key role. A variety of molecules are located at the apical membrane, but only a few key molecules act as determinants that are required to maintain the identity of the apical membrane and, thus, epithelial polarity. These molecules are the proteins Cdc42, atypical protein kinase C (aPKC), Par6, Par3/Bazooka/ASIP. Crumbs, "Stardust" and protein at tight junctions (PATJ). These molecules appear to form two distinct complexes: an aPKC-Par3-Par6 "aPKC" (or "Par") complex that also interacts with Cdc42; and a Crumbs-Stardust-PATJ "Crumbs" complex. Of these two complexes, the aPKC complex is the most important for epithelial polarity, being required even when the Crumbs complex is not. Crumbs is the only transmembrane protein in this list and the Crumbs complex serves as an apical cue to keep the aPKC complex apical during complex cellular shape changes.

Basolateral membranes

In the context of

renal tubule The nephron is the minute or microscopic structural and functional unit of the kidney. It is composed of a renal corpuscle and a renal tubule. The renal corpuscle consists of a tuft of capillaries called a glomerulus and a cup-shaped structure ca ...

physiology, the term basolateral membrane or serosal membrane refers to the

cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...

which is oriented ''away'' from the lumen of the tubule, whereas the term luminal membrane or apical membrane refers to the

which is oriented ''towards'' the lumen. The principal function of this basolateral membrane is to take up

metabolic Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...

waste products into the

epithelial cell Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellula ...

for disposal into the lumen where it is transported out of the body as

urine Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excretion, excreted from the body through the urethra. Cel ...

. A secondary role of the basolateral membrane is to allow the recycling of desirable substrates, such as

glucose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, using ...

, that have been rescued from the lumen of the tubule to be secreted into the

interstitial fluid In cell biology, extracellular fluid (ECF) denotes all body fluid outside the cells of any multicellular organism. Total body water in healthy adults is about 60% (range 45 to 75%) of total body weight; women and the obese typically have a lower ...

s. Basal and lateral membranes share common determinants, the proteins LLGL1,

DLG1 Discs large homolog 1 (DLG1), also known as synapse-associated protein 97 or SAP97, is a scaffold protein that in humans is encoded by the ''SAP97'' gene. SAP97 is a mammalian MAGUK-family member protein that is similar to the Drosophila protein ...

, and SCRIB. These three proteins all localize to the basolateral domain and are essential for basolateral identity and for epithelial polarity.

Mechanisms of polarity

How epithelial cells polarize is still not fully understood. Some key principles have been proposed to maintain polarity, but the mechanisms behind these principles remain to be discovered. The first principle is

positive feedback Positive feedback (exacerbating feedback, self-reinforcing feedback) is a process that occurs in a feedback loop which exacerbates the effects of a small disturbance. That is, the effects of a perturbation on a system include an increase in the ...

. In computer models, a molecule that can be either membrane-associated or cytoplasmic can polarize when its association with the membrane is subject to positive feedback: that membrane localization occurs most strongly where the molecule is already most highly concentrated. In similar models, researchers have shown that epithelial cells can self-assemble into a rich set of robust biological shapes. In the yeast

saccharomyces cerevisiae ''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungus microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have been o ...

, there is genetic evidence that Cdc42 is subject to positive feedback of this kind and can spontaneously polarize, even in the absence of an external cue. In the fruit fly

Drosophila melanogaster ''Drosophila melanogaster'' is a species of fly (the taxonomic order Diptera) in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the "vinegar fly" or "pomace fly". Starting with Ch ...

, Cdc42 is recruited by the aPKC complex and then promotes the apical localization of the aPKC complex in a probable positive feedback loop. Thus, in the absence of Cdc42 or the aPKC complex, apical determinants cannot be maintained at the apical membrane and consequently, apical identity and polarity is lost. The second principle is segregation of polarity determinants. The sharp distinction between apical and baso-lateral domains is maintained by an active mechanism that prevents mixing. The nature of this mechanism is not known, but it clearly depends on the polarity determinants. In the absence of the aPKC complex, the baso-lateral determinants spread into the former apical domain. Conversely, in the absence of any of Lgl, Dlg or Scrib, the apical determinants spread into the former baso-lateral domain. Thus, the two determinants behave as if they exert mutual repulsion upon one another. The third principle is directed

exocytosis Exocytosis () is a form of active transport and bulk transport in which a cell transports molecules (e.g., neurotransmitters and proteins) out of the cell ('' exo-'' + ''cytosis''). As an active transport mechanism, exocytosis requires the use o ...

. Apical membrane proteins are trafficked from the Golgi to the apical, rather than baso-lateral, membrane because apical determinants serve to identify the correct destination for

vesicle Vesicle may refer to: ; In cellular biology or chemistry * Vesicle (biology and chemistry), a supramolecular assembly of lipid molecules, like a cell membrane * Synaptic vesicle ; In human embryology * Vesicle (embryology), bulge-like features o ...

delivery. A related mechanism is likely to operate for the baso-lateral membranes. The fourth principle is lipid modification. A component of the lipid bilayer, phosphatidyl inositol phosphate (PIP) can be phosphorylated to form PIP₂ and PIP₃. In some epithelial cells, PIP₂ is apically localised while PIP₃ is basolaterally localised. In at least one cultured cell line, the MDCK cell, this system is required for epithelial polarity. The relationship between this system and the polarity determinants in animal tissues remains unclear.

Basal versus lateral

Since basal and lateral membranes share the same determinants, another mechanism must make the difference between the two domains. Cell shape and contacts provide the likely mechanism. Lateral membranes are the site of contact between epithelial cells, whereas basal membranes connect epithelial cells to the

basement membrane The basement membrane is a thin, pliable sheet-like type of extracellular matrix that provides cell and tissue support and acts as a platform for complex signalling. The basement membrane sits between Epithelium, epithelial tissues including mesot ...

, an extracellular matrix layer that lies along the basal surface of the epithelium. Certain molecules, such as

Integrin Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...

s, localise specifically to the basal membrane and form connections with the extracellular matrix.

Epithelial cell shape

Epithelial cells come in a variety of

shapes A shape or figure is a graphical representation of an object or its external boundary, outline, or external surface, as opposed to other properties such as color, texture, or material type. A plane shape or plane figure is constrained to lie on ...

that relate to their function in development or physiology. How epithelial cells adopt particular shapes is poorly understood, but it must involve spatial control of the

actin cytoskeleton Microfilaments, also called actin filaments, are protein filaments in the cytoplasm of eukaryotic cells that form part of the cytoskeleton. They are primarily composed of polymers of actin, but are modified by and interact with numerous other pr ...

, which is central to cell shape in all plant cells.

Epithelial cadherin

All epithelial cells express the transmembrane

adhesion molecule Cell adhesion molecules (CAMs) are a subset of cell surface proteins that are involved in the binding of cells with other cells or with the extracellular matrix (ECM), in a process called cell adhesion. In essence, CAMs help cells stick to each ...

E-cadherin Cadherin-1 or Epithelial cadherin (E-cadherin), (not to be confused with the APC/C activator protein CDH1) is a protein that in humans is encoded by the ''CDH1'' gene. Mutations are correlated with gastric, breast, colorectal, thyroid, and ovarian ...

, a

cadherin Cadherins (named for "calcium-dependent adhesion") are a type of cell adhesion molecule (CAM) that is important in the formation of adherens junctions to allow cells to adhere to each other . Cadherins are a class of type-1 transmembrane proteins, ...

which localises most prominently to the junction between the apical and lateral membranes. The extra-cellular domains of E-cadherin molecules from neighbouring cells bind to one another via a homotypic interaction. The intra-cellular domains of E-cadherin molecules bind to the

via the adaptor proteins

alpha-catenin Alpha-catenin functions as the primary protein link between cadherins and the actin cytoskeleton. It has been reported that the actin binding proteins vinculin and alpha-actinin can bind to alpha-catenin. It has been suggested that alpha-caten ...

and

beta-catenin Catenin beta-1, also known as beta-catenin (β-catenin), is a protein that in humans is encoded by the ''CTNNB1'' gene. Beta-catenin is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcripti ...

. Thus, E-cadherin forms

adherens junctions Adherens junctions (or zonula adherens, intermediate junction, or "belt desmosome") are protein complexes that occur at cell–cell junctions, cell–matrix junctions in epithelial and endothelial tissues, usually more basal than tight junctions. ...

that connect the actin cytoskeletons of neighbouring cells. Adherens junctions are the primary force-bearing junctions between epithelial cells and are fundamentally important for maintaining epithelial cell shape and for dynamic changes in shape during tissue development. How E-cadherin localizes to the boundary between apical and lateral membranes is not known, but polarized membranes are essential for maintaining E-cadherin at adherens junctions.

References