Asymmetric cell division

Last updated December 03, 2023

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. (In times of growth or regeneration, stem cells can also divide symmetrically, to produce two identical copies of the original cell.^[1])

In principle, there are two mechanisms by which distinct properties may be conferred on the daughters of a dividing cell. In one, the daughter cells are initially equivalent but a difference is induced by signaling between the cells, from surrounding cells, or from the precursor cell. This mechanism is known as extrinsic asymmetric cell division. In the second mechanism, the prospective daughter cells are inherently different at the time of division of the mother cell. Because this latter mechanism does not depend on interactions of cells with each other or with their environment, it must rely on intrinsic asymmetry. The term asymmetric cell division usually refers to such intrinsic asymmetric divisions.^[2]

Intrinsic asymmetry

In order for asymmetric division to take place the mother cell must be polarized, and the mitotic spindle must be aligned with the axis of polarity. The cell biology of these events has been most studied in three animal models: the mouse, the nematode Caenorhabditis elegans , and the fruit fly Drosophila melanogaster . A later focus has been on development in spiralia.

In C. elegans development

Asymmetric cell divisions during the first steps of the embryogenesis of C. elegans

In C. elegans, a series of asymmetric cell divisions in the early embryo are critical in setting up the anterior/posterior, dorsal/ventral, and left/right axes of the body plan.^[3] After fertilization, events are already occurring in the zygote to allow for the first asymmetric cell division. This first division produces two distinctly different blastomeres, termed AB and P1. When the sperm cell fertilizes the egg cell, the sperm pronucleus and centrosomes are deposited within the egg, which causes a cytoplasmic flux resulting in the movement of the pronucleus and centrosomes towards one pole.^[4] The centrosomes deposited by the sperm are responsible for the establishment of the posterior pole within the zygote.^[5] Sperm with mutant or absent centrosomes fail to establish a posterior pole.^[6]^[7]^[8] The establishment of this polarity initiates the polarized distribution of a group of proteins present in the zygote called the PARD proteins (partitioning defective), which are a conserved group of proteins that function in establishing cell polarity during development.^[9] These proteins are initially distributed uniformly throughout the zygote and then become polarized with the creation of the posterior pole. This series of events allows the single celled zygote to obtain polarity through an unequal distribution of multiple factors.

The single cell is now set up to undergo an asymmetric cell division, however the orientation in which the division occurs is also an important factor. The mitotic spindle must be oriented correctly to ensure that the proper cell fate determinants are distributed appropriately to the daughter cells. The alignment of the spindle is mediated by the PARD proteins, which regulate the positioning of the centrosomes along the A/P axis as well as the movement of the mitotic spindle along the A/P axis.^[3] Following this first asymmetric division, the AB daughter cell divides symmetrically, giving rise to ABa and ABp, while the P1 daughter cell undergoes another asymmetric cell division to produce P2 and EMS. This division is also dependent on the distribution of the PAR proteins.^[10]

In Drosophila neural development

In Drosophila melanogaster, asymmetric cell division plays an important role in neural development. Neuroblasts are the progenitor cells which divide asymmetrically to give rise to another neuroblast and a ganglion mother cell (GMC). The neuroblast repeatedly undergoes this asymmetric cell division while the GMC continues on to produce a pair of neurons. Two proteins play an important role in setting up this cell fate asymmetry in the neuroblast, Prospero and Numb. These proteins are both synthesized in the neuroblast and segregate into only the GMC during divisions.^[11] Numb is a suppressor of Notch, therefore the asymmetric segregation of Numb to the basal cortex biases the response of the daughter cells to Notch signaling, resulting in two distinct cell fates.^[12] Prospero is required for gene regulation in GMCs. It is equally distributed throughout the neuroblast cytoplasm, but becomes localized at the basal cortex when the neuroblast starts to undergo mitosis. Once the GMC buds off from the basal cortex, Prospero becomes translocated into the GMC nucleus to act as a transcription factor.^[11]

Other proteins present in the neuroblast mediate the asymmetric localization of Numb and Prospero. Miranda is an anchoring protein that binds to Prospero and keeps it in the basal cortex. Following the generation of the GMC, Miranda releases Prospero and then becomes degraded.^[11]^[13] The segregation of Numb is mediated by Pon (the partner of Numb protein). Pon binds to Numb and colocalizes with it during neuroblast cell division.^[11]

The mitotic spindle must also align parallel to the asymmetrically distributed cell fate determinants to allow them to become segregated into one daughter cell and not the other. The mitotic spindle orientation is mediated by Inscuteable, which is segregated to the apical cortex of the neuroblast. Without the presence of Inscuteable, the positioning of the mitotic spindle and the cell fate determinants in relationship to each other becomes randomized. Inscuteable mutants display a uniform distribution of Miranda and Numb at the cortex, and the resulting daughter cells display identical neuronal fates.^[11]

In addition to the two daughter cells having separate fates, they have different cell sizes; the resulting neuroblast is much larger than the GMC.^[14] However, unlike with the proper segregation of fate determinants, asymmetric cell division that gives rise to cell size asymmetry is spindle-independent.^[15]^[16] The mechanism instead relies on the spatial and temporal organization of myosin on the cell cortex and its upstream components. Apical localization of Pins (Partner of Inscuteable) by Inscuteable allows Pins-dependent apical Protein Kinase N (Pkn) localization during metaphase. Pkn inhibits Rho-kinase (Rok), resulting in the timely loss of myosin and Rok from the apical cortex at anaphase onset.^[17]^[18]^[19] The apical myosin flows basally to where the cleavage furrow is positioned. Subsequently, the proteins Tum and Pav at the central spindle recruit myosin to increase myosin concentration, generating a myosin gradient to drive apical myosin flow from the basal cortex.^[19]^[20] This spatiotemporal control of myosin localization results in the asymmetric loss of cortical tension that normally pushes against hydrostatic pressure. In other words, the loss of apical cortical myosin allows hydrostatic pressure to push against the apical cell membrane, increasing the size of the apical region that is bound to become the larger neuroblast after cell division.^[14]^[19] Generation of apical and basal myosin flows simultaneously results in symmetric cell division, and delaying of basal myosin flows prevents normal expansion of the basal region of the dividing cell.^[14]^[19] Although this mechanism is spindle-independent, the spindle is important for setting up the cleavage furrow position, for bringing myosin to the cleavage furrow, and for driving basal myosin clearing.^[14]^[19]

Actomyosin-based cortical flows direct a reorganization of the plasma membrane and cell cortex of the neuroblast, which is needed to generate the size difference between daughter cells.^[21]^[22]^[23]^[24] Early in mitosis, cortical flows collect membrane folds and protrusions around the apical pole forming a polarized membrane reservoir.^[21]^[22] As myosin clears from the apical cortex and cleavage furrow ingression causes hydrostatic pressure to increase, the stores of membrane within the reservoir are used to expand the apical region which becomes the larger daughter cell after division.^[21]

In spiralian development

Spiralia (commonly synonymous with lophotrochozoa) represent a diverse clade of animals whose species comprise the bulk of the bilaterian animals present today. Examples include mollusks, annelid worms, and the entoprocta. Although much is known at the cellular and molecular level about the other bilateralian clades (ecdysozoa and deuterostomia), research into the processes that govern spiralian development is comparatively lacking. However, one unifying feature shared among spiralia is the pattern of cleavage in the early embryo known as spiral cleavage.^[25]

Mechanisms of asymmetric division (See Figure, right panel):

Tubifex tubifex: The sludge worm Tubifex tubifex has been shown to demonstrate an interesting asymmetric cell division at the point of first embryonic cleavage. Unlike the classic idea of cortical differences at the zygotic membrane that determine spindle asymmetry in the C. elegans embryo, the first cleavage in tubifex relies on the number of centrosomes.^[26] Embryos inherit a single centrosome which localizes in the prospective larger CD cell cytoplasm and emits radial microtubules during anaphase that contribute to both the mitotic spindle as well as cortical asters. However, the microtubule organizing center of the prospective smaller AB cell emits only microtubules that commit to the mitotic spindle and not cortical bound asters. When embryos are compressed or deformed, asymmetric spindles still form, and staining for gamma tubulin reveals that the second microtubule organizing center lacks the molecular signature of a centrosome. Furthermore, when centrosome number is doubled, tubifex embryos cleave symmetrically, suggesting this monoastral mechanism of asymmetric cell division is centrosome dependent.^[26]
Helobdella robusta: The leech Helobdella robusta exhibits a similar asymmetry in the first embryonic division as C. elegans and tubifex, but relies on a modified mechanism. Compression experiments on the robusta embryo do not affect asymmetric division, suggesting the mechanism, like tubifex, uses a cortical independent molecular pathway. In robusta, antibody staining reveals that the mitotic spindle forms symmetrically until metaphase and stems from two biastral centrosomes.^[27] At the onset of metaphase, asymmetry becomes apparent as the centrosome of the prospective larger CD cell lengthens cortical asters while the asters of the prospective smaller AB cell become downregulated. Experiments using nocodazole and taxol support this observation. Taxol, which stabilized microtubules, forced a significant number of embryos to cleave symmetrically when used at a moderate concentration. Moreover, embryos treated with nocodazole, which sequesters tubulin dimers and promotes microtubule depolymerization, similarly forced symmetric division in a significant number of embryos. Treatment with either drug at these concentrations fails to disrupt normal centrosome dynamics, suggesting that a balance of microtubule polymerization and depolymerization represents another mechanism for establishing asymmetric cell division in spilarian development.^[27]
Ilyanasa obsoleta: A third, less traditional mechanism contributing to asymmetric cell division in spiralian development has been discovered in the mollusk Ilyanasa obsoleta . In situ hybridization and immunofluorescence experiments show that mRNA transcripts co-localize with centrosomes during early cleavage.^[28] Consequently, these transcripts are inherited in a stereotypical fashion to distinct cells. All mRNA transcripts followed have been implicated in body axis patterning, and in situ hybridization for transcripts associated with other functions fail to exhibit such a localization. Moreover, disruption of microtubule polymerization with nocodazole, and of actin polymerization with cytochalisin B, shows the cytoskeleton is also important in this asymmetry. It appears that microtubules are not required to recruit the mRNA to the centrosome, and that actin is required to attach the centrosome to the cortex. Finally, introducing multiple centrosomes into one cell by inhibiting cytokinesis shows that mRNA dependably localizes on the correct centrosome, suggesting intrinsic differences between each centrosomal composition. It is important to note that these results reflect experiments performed after the first two divisions, yet still demonstrate a different molecular means of establishing asymmetry in a dividing cell.^[28]

In stem cells and progenitors

Animals are made up of a vast number of distinct cell types. During development, the zygote undergoes many cell divisions that give rise to various cell types, including embryonic stem cells. Asymmetric divisions of these embryonic cells gives rise to one cell of the same potency (self-renewal), and another that maybe of the same potency or stimulated to further differentiate into specialized cell types such as neurons. This stimulated differentiation arises from many factors which can be divided into two broad categories: intrinsic and extrinsic. Intrinsic factors generally involve differing amounts of cell-fate determinants being distributed into each daughter cell. Extrinsic factors involve interactions with neighboring cells and the micro and macro environment of the precursor cell.^[29]

In addition to the aforementioned Drosophila neuronal example, it was proposed that the macrosensory organs of the Drosophila, specifically the glial cells, also arise from a similar set of asymmetric division from a single progenitor cell via regulation of the Notch signaling pathway and transcription factors.^[30] An example of how extrinsic factors bring about this phenomenon is the physical displacement of one of the daughter cells out of the original stem cell niche, exposing it to signalling molecules such as chondroitin sulfate.^[31] In this manner, the daughter cell is forced to interact with the heavily sulfated molecules, which stimulate it to differentiate while the other daughter cell remains in the original niche in a quiescent state.

Role in disease

In normal stem and progenitor cells, asymmetric cell division balances proliferation and self-renewal with cell-cycle exit and differentiation. Disruption of asymmetric cell division leads to aberrant self-renewal and impairs differentiation, and could therefore constitute an early step in the tumorogenic transformation of stem and progenitor cells. In normal non-tumor stem cells, a number of genes have been described which are responsible for pluripotency, such as Bmi-1, Wnt and Notch. These genes have been discovered also in the case of cancer stem cells, and shows that their aberrant expression is essential for the formation of tumor cell mass.^[32] For example, it has been shown that gastrointestinal cancers contain rare subpopulation of cancer stem cells which are capable to divide asymmetrically. The asymmetric division in these cells is regulated by cancer niche (microenvironment) and Wnt pathway. Blocking the Wnt pathway with IWP2 (WNT antagonist) or siRNA-TCF4 resulted in high suppression of asymmetric cell division.^[33]

Another mutation in asymmetric cell divisions which are involved in tumor growth are loss-of-function mutations. The first suggestion that loss of asymmetric cell division might be involved in tumorigenesis came from studies of Drosophila. Studies of loss-of-function mutations in key regulators of asymmetric cell division including lgl, aurA, polo, numb and brat, revealed hyperproliferative phenotypes in situ. In these mutants cells divide more symmetrically and generate mis-specified progeny that fail to exit the cell cycle and differentiate, but rather proliferate continuously and form a tumor cell mass.^[34]

Related Research Articles

In cell biology a centriole is a cylindrical organelle composed mainly of a protein called tubulin. Centrioles are found in most eukaryotic cells, but are not present in conifers (Pinophyta), flowering plants (angiosperms) and most fungi, and are only present in the male gametes of charophytes, bryophytes, seedless vascular plants, cycads, and Ginkgo. A bound pair of centrioles, surrounded by a highly ordered mass of dense material, called the pericentriolar material (PCM), makes up a structure called a centrosome.

Mitosis is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis is an equational division which gives rise to genetically identical cells in which the total number of chromosomes is maintained. Mitosis is preceded by the S phase of interphase and is followed by telophase and cytokinesis; which divides the cytoplasm, organelles and cell membrane of one cell into two new cells containing roughly equal shares of these cellular components. The different stages of mitosis altogether define the mitotic phase of a cell cycle—the division of the mother cell into two daughter cells genetically identical to each other.

Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27 nm and have an inner diameter between 11 and 15 nm. They are formed by the polymerization of a dimer of two globular proteins, alpha and beta tubulin into protofilaments that can then associate laterally to form a hollow tube, the microtubule. The most common form of a microtubule consists of 13 protofilaments in the tubular arrangement.

In cell biology, the centrosome is an organelle that serves as the main microtubule organizing center (MTOC) of the animal cell, as well as a regulator of cell-cycle progression. The centrosome provides structure for the cell. The centrosome is thought to have evolved only in the metazoan lineage of eukaryotic cells. Fungi and plants lack centrosomes and therefore use other structures to organize their microtubules. Although the centrosome has a key role in efficient mitosis in animal cells, it is not essential in certain fly and flatworm species.

Cytokinesis is the part of the cell division process during which the cytoplasm of a single eukaryotic cell divides into two daughter cells. Cytoplasmic division begins during or after the late stages of nuclear division in mitosis and meiosis. During cytokinesis the spindle apparatus partitions and transports duplicated chromatids into the cytoplasm of the separating daughter cells. It thereby ensures that chromosome number and complement are maintained from one generation to the next and that, except in special cases, the daughter cells will be functional copies of the parent cell. After the completion of the telophase and cytokinesis, each daughter cell enters the interphase of the cell cycle.

<span class="mw-page-title-main">Spindle apparatus</span> Feature of biological cell structure

In cell biology, the spindle apparatus is the cytoskeletal structure of eukaryotic cells that forms during cell division to separate sister chromatids between daughter cells. It is referred to as the mitotic spindle during mitosis, a process that produces genetically identical daughter cells, or the meiotic spindle during meiosis, a process that produces gametes with half the number of chromosomes of the parent cell.

<span class="mw-page-title-main">Cleavage furrow</span> Plasma membrane invagination at the cell division site

In cell biology, the cleavage furrow is the indentation of the cell's surface that begins the progression of cleavage, by which animal and some algal cells undergo cytokinesis, the final splitting of the membrane, in the process of cell division. The same proteins responsible for muscle contraction, actin and myosin, begin the process of forming the cleavage furrow, creating an actomyosin ring. Other cytoskeletal proteins and actin binding proteins are involved in the procedure.

In biology, a blastomere is a type of cell produced by cell division (cleavage) of the zygote after fertilization; blastomeres are an essential part of blastula formation, and blastocyst formation in mammals.

<span class="mw-page-title-main">Cell cortex</span> Layer on the inner face of a cell membrane

The cell cortex, also known as the actin cortex, cortical cytoskeleton or actomyosin cortex, is a specialized layer of cytoplasmic proteins on the inner face of the cell membrane. It functions as a modulator of membrane behavior and cell surface properties. In most eukaryotic cells lacking a cell wall, the cortex is an actin-rich network consisting of F-actin filaments, myosin motors, and actin-binding proteins. The actomyosin cortex is attached to the cell membrane via membrane-anchoring proteins called ERM proteins that plays a central role in cell shape control. The protein constituents of the cortex undergo rapid turnover, making the cortex both mechanically rigid and highly plastic, two properties essential to its function. In most cases, the cortex is in the range of 100 to 1000 nanometers thick.

Aurora kinase A also known as serine/threonine-protein kinase 6 is an enzyme that in humans is encoded by the AURKA gene.

In cell biology, microtubule nucleation is the event that initiates de novo formation of microtubules (MTs). These filaments of the cytoskeleton typically form through polymerization of α- and β-tubulin dimers, the basic building blocks of the microtubule, which initially interact to nucleate a seed from which the filament elongates.

Aurora kinase B is a protein that functions in the attachment of the mitotic spindle to the centromere.

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.

Anillin is a conserved protein implicated in cytoskeletal dynamics during cellularization and cytokinesis. The ANLN gene in humans and the scraps gene in Drosophila encode Anillin. In 1989, anillin was first isolated in embryos of Drosophila melanogaster. It was identified as an F-actin binding protein. Six years later, the anillin gene was cloned from cDNA originating from a Drosophila ovary. Staining with anti-anillin antibody showed the anillin localizes to the nucleus during interphase and to the contractile ring during cytokinesis. These observations agree with further research that found anillin in high concentrations near the cleavage furrow coinciding with RhoA, a key regulator of contractile ring formation.

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.

An aster is a cellular structure shaped like a star, consisting of a centrosome and its associated microtubules during the early stages of mitosis in an animal cell. Asters do not form during mitosis in plants. Astral rays, composed of microtubules, radiate from the centrosphere and look like a cloud. Astral rays are one variant of microtubule which comes out of the centrosome; others include kinetochore microtubules and polar microtubules.

<span class="mw-page-title-main">Ganglion mother cell</span>

Ganglion mother cells (GMCs) are cells involved in neurogenesis, in non-mammals, that divide only once to give rise to two neurons, or one neuron and one glial cell or two glial cells, and are present only in the central nervous system. They are also responsible for transcription factor expression. While each ganglion mother cell necessarily gives rise to two neurons, a neuroblast can asymmetrically divide multiple times. GMCs are the progeny of type I neuroblasts. Neuroblasts asymmetrically divide during embryogenesis to create GMCs. GMCs are only present in certain species and only during the embryonic and larval stages of life. Recent research has shown that there is an intermediate stage between a GMC and two neurons. The GMC forms two ganglion cells which then develop into neurons or glial cells. Embryonic neurogenesis has been extensively studied in Drosophila melanogaster embryos and larvae.

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">Anthony A. Hyman</span> British biologist

Anthony Arie Hyman is a British scientist and director at the Max Planck Institute of Molecular Cell Biology and Genetics.

The fusome is a membranous structure found in the developing germ cell cysts of many insect orders. Initial description of the fusome occurred in the 19th century and since then the fusome has been extensively studied in Drosophila melanogaster male and female germline development. This structure has roles in maintaining germline cysts, coordinating the number of mitotic divisions prior to meiosis, and oocyte determination by serving as a structure for intercellular communication.

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