Cell polarity

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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 described below, including epithelial cells with apical-basal polarity, neurons in which signals propagate in one direction from dendrites to axons, and migrating cells. Furthermore, cell polarity is important during many types of asymmetric cell division to set up functional asymmetries between daughter cells.

Contents

Many of the key molecular players implicated in cell polarity are well conserved. For example, in metazoan 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]

Polarized localization of Staufen protein (white arrow) in Drosophila stage 9 oocyte (Stau:GFP, DAPI). Stauffen Yu etal.png
Polarized localization of Staufen protein (white arrow) in Drosophila stage 9 oocyte (Stau:GFP, DAPI).

Examples of polarized cells

Epithelial cells

Epithelial cells adhere to one another through tight junctions, desmosomes and adherens 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 the apical membrane facing the outside surface of the body, or the lumen of internal cavities, and the basolateral 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 the basement membrane, a thin sheet of extracellular matrix proteins that separates the epithelial sheet from underlying cells and connective tissue. Epithelial cells also exhibit planar 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]

Neurons

A neuron receives signals from neighboring cells through branched, cellular extensions called dendrites. The neuron then propagates an electrical signal down a specialized axon 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]

Migratory cells

Many cell types are capable of migration, such as leukocytes and fibroblasts, 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 the lamellipodium or thin protrusions called filopodia. 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 actin microfilaments, called stress 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]

Budding yeast

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. [7] In the absence of polarity landmarks (i.e. in gene deletion mutants), cells can perform spontaneous symmetry breaking, [8] 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 is Cdc42, which is a member of the eukaryotic Ras-homologous Rho-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 its guanine nucleotide exchange factor (GEF), Cdc24, and by its GTPase-activating proteins (GAPs). Cdc42 localization is further regulated by cell cycle queues, and a number of binding partners. [9] A recent study to elucidate the connection between cell cycle timing and Cdc42 accumulation in the bud site uses optogenetics to control protein localization using light. [10] During mating, these polarity sites can relocate. Mathematical modeling coupled with imaging experiments suggest the relocation is mediated by actin-driven vesicle delivery. [11] [12]

Vertebrate development

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.

Molecular basis

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]

Polarity establishment

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.

See also

Related Research Articles

The exocyst is an octameric protein complex involved in vesicle trafficking, specifically the tethering and spatial targeting of post-Golgi vesicles to the plasma membrane prior to vesicle fusion. It is implicated in a number of cell processes, including exocytosis, cell migration, and growth.

An asymmetric cell division produces two daughter cells with different cellular fates. This is in contrast to symmetric cell divisions which give rise to daughter cells of equivalent fates. Notably, stem cells divide asymmetrically to give rise to two distinct daughter cells: one copy of the original stem cell as well as a second daughter programmed to differentiate into a non-stem cell fate.

The Rho family of GTPases is a family of small signaling G proteins, and is a subfamily of the Ras superfamily. The members of the Rho GTPase family have been shown to regulate many aspects of intracellular actin dynamics, and are found in all eukaryotic kingdoms, including yeasts and some plants. Three members of the family have been studied in detail: Cdc42, Rac1, and RhoA. All G proteins are "molecular switches", and Rho proteins play a role in organelle development, cytoskeletal dynamics, cell movement, and other common cellular functions.

<span class="mw-page-title-main">CDC42</span> Protein-coding gene in the species Homo sapiens

Cell division control protein 42 homolog is a protein that in humans is encoded by the CDC42 gene. Cdc42 is involved in regulation of the cell cycle. It was originally identified in S. cerevisiae (yeast) as a mediator of cell division, and is now known to influence a variety of signaling events and cellular processes in a variety of organisms from yeast to mammals.

<span class="mw-page-title-main">FGD1</span> Protein-coding gene in the species Homo sapiens

FYVE, RhoGEF and PH domain-containing protein 1 (FGD1) also known as faciogenital dysplasia 1 protein (FGDY), zinc finger FYVE domain-containing protein 3 (ZFYVE3), or Rho/Rac guanine nucleotide exchange factor FGD1 is a protein that in humans is encoded by the FGD1 gene that lies on the X chromosome. Orthologs of the FGD1 gene are found in dog, cow, mouse, rat, and zebrafish, and also budding yeast and C. elegans. It is a member of the FYVE, RhoGEF and PH domain containing family.

<span class="mw-page-title-main">Transforming protein RhoA</span> Protein and coding gene in humans

Transforming protein RhoA, also known as Ras homolog family member A (RhoA), is a small GTPase protein in the Rho family of GTPases that in humans is encoded by the RHOA gene. While the effects of RhoA activity are not all well known, it is primarily associated with cytoskeleton regulation, mostly actin stress fibers formation and actomyosin contractility. It acts upon several effectors. Among them, ROCK1 and DIAPH1 are the best described. RhoA, and the other Rho GTPases, are part of a larger family of related proteins known as the Ras superfamily, a family of proteins involved in the regulation and timing of cell division. RhoA is one of the oldest Rho GTPases, with homologues present in the genomes since 1.5 billion years. As a consequence, RhoA is somehow involved in many cellular processes which emerged throughout evolution. RhoA specifically is regarded as a prominent regulatory factor in other functions such as the regulation of cytoskeletal dynamics, transcription, cell cycle progression and cell transformation.

<span class="mw-page-title-main">NUMB (gene)</span> Protein-coding gene in the species Homo sapiens

Protein numb homolog is a protein that in humans is encoded by the NUMB gene. The protein encoded by this gene plays a role in the determination of cell fates during development. The encoded protein, whose degradation is induced in a proteasome-dependent manner by MDM2, is a membrane-bound protein that has been shown to associate with EPS15, LNX1, and NOTCH1. Four transcript variants encoding different isoforms have been found for this gene.

<span class="mw-page-title-main">PARD3</span> Protein-coding gene in the species Homo sapiens

Partitioning defective 3 homolog is a protein that in humans is encoded by the PARD3 gene.

<span class="mw-page-title-main">SCRIB</span> Protein-coding gene in the species Homo sapiens

SCRIB, also known as Scribble, SCRIBL, or Scribbled homolog (Drosophila), is a scaffold protein which in humans is encoded by the SCRIB gene. It was originally isolated in Drosophila melanogaster in a pathway (also known as the Scribble complex) with DLGAP5 (Discs large) and LLGL1 (Lethal giant larvae) as a tumor suppressor. In humans, SCRIB is found as a membrane protein and is involved in cell migration, cell polarity, and cell proliferation in epithelial cells. There is also strong evidence that SCRIB may play a role in cancer progression because of its strong homology to the Drosophila protein.

<span class="mw-page-title-main">PARD6A</span> Protein-coding gene in the species Homo sapiens

Partitioning defective 6 homolog alpha is a protein that in humans is encoded by the PARD6A gene.

<span class="mw-page-title-main">PARD6B</span> Protein-coding gene in the species Homo sapiens

Partitioning defective 6 homolog beta is a protein that in humans is encoded by the PARD6B gene.

<span class="mw-page-title-main">Planar cell polarity</span>

Planar cell polarity (PCP) is the protein-mediated signaling that coordinates the orientation of cells in a layer of epithelial tissue. In vertebrates, examples of mature PCP oriented tissue are the stereo-cilia bundles in the inner ear, motile cilia of the epithelium, and cell motility in epidermal wound healing. Additionally, PCP is known to be crucial to major developmental time points including coordinating convergent extension during gastrulation and coordinating cell behavior for neural tube closure. Cells orient themselves and their neighbors by establishing asymmetric expression of PCP components on opposing cell members within cells to establish and maintain the directionality of the cells. Some of these PCP components are transmembrane proteins which can proliferate the orientation signal to the surrounding cells.

<span class="mw-page-title-main">Cingulin-like protein 1</span> Protein found in humans

Cingulin-like protein 1, also known as paracingulin or junction-associated-coiled-coil protein (JACOP), is a protein which is encoded by the CGNL1 gene.

Epithelial polarity is one example of the cell polarity that is a fundamental feature of many types of cells. Epithelial cells feature distinct 'apical', 'lateral' and 'basal' plasma membrane 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.

Symmetry breaking in biology is the process by which uniformity is broken, or the number of points to view invariance are reduced, to generate a more structured and improbable state. Symmetry breaking is the event where symmetry along a particular axis is lost to establish a polarity. Polarity is a measure for a biological system to distinguish poles along an axis. This measure is important because it is the first step to building complexity. For example, during organismal development, one of the first steps for the embryo is to distinguish its dorsal-ventral axis. The symmetry-breaking event that occurs here will determine which end of this axis will be the ventral side, and which end will be the dorsal side. Once this distinction is made, then all the structures that are located along this axis can develop at the proper location. As an example, during human development, the embryo needs to establish where is ‘back’ and where is ‘front’ before complex structures, such as the spine and lungs, can develop in the right location. This relationship between symmetry breaking and complexity was articulated by P.W. Anderson. He speculated that increasing levels of broken symmetry in many-body systems correlates with increasing complexity and functional specialization. In a biological perspective, the more complex an organism is, the higher number of symmetry-breaking events can be found.

<span class="mw-page-title-main">Germ-band extension</span>

Germ-band extension is a morphological process widely studied in Drosophila melanogaster in which the germ-band, which develops into the segmented trunk of the embryo, approximately doubles in length along the anterior-posterior axis while subsequently narrowing along the dorsal-ventral axis.

<span class="mw-page-title-main">KIN2/PAR-1/MARK kinase family</span> Family of protein kinases

In molecular biology, members of the KIN2/PAR-1/MARK kinase family of proteins are kinases that are conserved from yeast to human and share the same domain organisation: an N-terminal kinase domain and a C-terminal kinase associated domain 1 (KA1). Some members of this family also contain an UBA domain. Members of this kinase family are involved in various biological processes such as cell polarity, cell cycle control, intracellular signalling, microtubule stability and protein stability. The function of the KA1 domain is not yet known.

NDR kinases, are an ancient and highly conserved subclass of AGC protein kinases that control diverse processes related to cell morphogenesis, proliferation, and mitotic events.

Shigeo Ohno is a Japanese molecular biologist known for his pioneer research on Protein Kinase C (PKC) and Cell Polarity. His works led to the fundamental understanding of cell polarity in response to cell signaling.

Barry James Thompson is an Australian and British developmental biologist and cancer biologist. Thompson is known for identifying genes, proteins and mechanisms involved in epithelial polarity, morphogenesis and cell signaling via the Wnt and Hippo signaling pathways, which have key roles in human cancer.

References

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  5. ↑ Ridley, Anne J.; Schwartz, Martin A.; Burridge, Keith; Firtel, Richard A.; Ginsberg, Mark H.; Borisy, Gary; Parsons, J. Thomas; Horwitz, Alan Rick (5 December 2003). "Cell Migration: Integrating Signals from Front to back". Science. 302 (5651): 1704–1709. doi:10.1126/science.1092053. PMID   14657486. S2CID   16029926.
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  21. ↑ Turing, A. M.; S, F. R. (1952-08-14). "The chemical basis of morphogenesis". Phil. Trans. R. Soc. Lond. B. 237 (641): 37–72. doi:10.1098/rstb.1952.0012. ISSN   0080-4622.
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