An asymmetric cell division produces two daughter cells with different cellular fates. This is in contrast to normal, 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 original stem cell as well as a second daughter programmed to differentiate into a nment, it must rely on intrinsic asymmetry. The term asymmetric cell division usually refers to such intrinsic asymmetric divisions [1]
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Intrinsic asymmetric divisions but they follow mechanism. At mitosis certain proteins, RNA transcripts, and other macromolecules are localized asymmetrically to one half of the cell. A cell can accomplish this through a variety of processes such as localized molecule tethering as well as molecule transport (see below). Following this, the cell performs cytokinesis and divides in two. Thus, the asymmetrically localized proteins, RNA transcripts, and other macromolecules are inherited differentially to only one of the daughter cells, causing that cell to assume a separate fate from its sibling. Because these molecules ultimately determine the identity of the daughter cell they are called cell fate determinants.
This mechanism raises two requirements: first, the mother cell must be polarized; second, the mitotic spindle must be aligned with the axis of polarity. The cell biology of these events has been most traditionally studied in three animal models: the mouse, the nematode Caenorhabditis elegans and the fruitfly Drosophila melanogaster. Recent work in spiralian development has also discovered insightful mechanisms of asymmetric cell division
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.[2] After fertilization, events are already occurring in the one cell stage embryo to allow for the first asymmetric cell division. This first division produces two distinctly different blastomeres, termed AB and P1. When the sperm fertilizes the egg, the sperm nucleus and centrosomes are deposited within the egg, which causes a cytoplasmic flux resulting in the movement of the sperm pronucleus and centrosomes towards one pole.[3] The centrosomes deposited by the sperm seem to be responsible for the establishment of the posterior pole within the one cell embryo. Studies have shown that the pole in which the sperm-derived centrosomes reside always becomes the posterior pole. Furthermore, sperm with mutant or absent centrosomes fail to establish a posterior pole, while enucleated sperm with intact centrosomes successfully fertilize the egg and set up the posterior pole.[4][5] The establishment of this polarity initiates the polarized distribution of a group of proteins present in the zygote called the PAR proteins (partitioning-defective), which are a conserved group of proteins that function in establishing cell polarity during development.[6] 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 PAR 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.[7] 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.[8]
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 asymmetry in the neuroblast, Prospero and Numb. These proteins are both synthesized in the neuroblast and segregate into only the GMC during divisions.[9] 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.[10] 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.[9]
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.[9][11] 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.[9]
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.[9]
Spiralia(commonly synonymous with lophotrochozoa) represent a diverse clade of metazoan organisms 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.[12] This pattern, which contributed to the initial phylogenetic placement of this group of organisms, depends heavily on asymmetric cell division.
The general cleavage pattern of a spiralian embryo follows a classic and predictable set of cellular divisions. The first two divisions yield four progenitor macromeres which specify four geometric quadrants of the developing organism. Following this, the individual macromeres undergo a series of divisions which generate a string of micromeres at the animal pole of the embryo. Micromere production occurs in an alternating clockwise and counterclockwise fashion and is accomplished via asymmetric division.[12] For more information on this pattern of cellular division see the cleavage (embryo) page.
Although the conserved cleavage of spiralian macromeres to generate micromere quartets is well established, more has been discovered about the first two cleavages at the molecular level. The initial cleavage can occur with several, sometimes overlapping, outcomes (See Figure, left panel). For example, in symmetrically cleaving embryos, the zygote can cleave twice to yield four cells of equal size and equipotent fate.[12] In contrast, asymmetrically cleaving spiralians develop an embryonic polarity beginning with the first cellular division. The zygote cleaves once to generate a smaller AB cell and a larger CD cell. The second division usually occurs asynchronously, and generates three similarly sized macromeres (A, B, and C) as well as a larger D macromere. Known as D quadrant specification, this example of asymmetric cell division sets up the D quadrant of the embryo such that it has a specific and independent fate, often for mesoderm production.[12]
Mechanisms of asymmetric division (See Figure, right panel):
These examples of mechanisms that establish asymmetric cell division in early spiralian development showcase the plasticity of evolution. A variety of methods can contribute to differences in daughter cells in order to found independent cell fates.
Animals are made up of a vast number of distinct cell types. During development these are generated from a single cell, the zygote. Asymmetric divisions contribute to this expansion in cell type diversity by making two types of cells from one. For example, it is thought that many of the cells in the central nervous system derive from asymmetric divisions.
Cells may divide asymmetrically to produce two novel cells at the expense of the mother cell. For example, in plants, an asymmetric division of an unspecialized epidermal cell can produce a guard cell mother cell that divides again to produce two guard cells, the cells that control the closing and opening of stomata. However, asymmetric divisions often give rise to only one novel cell type in addition to a new copy of the mother cell. Such divisions are called self-renewing. Self-renewal is a hallmark of stem cells, and there is growing evidence that stem cells self-renew through asymmetric division. In this way the production of new cell types (differentiation) is precisely balanced by renewal of the stem cell population.
Asymmetric division of somatic cells also creates a drift in cell function through the human life span contributing to aging of the organism. It is due to the asymmetric distribution of DNA between daughter cells.
Asymmetric Cell Division, Progress in Molecular and Subcellular Biology, volume 45, A. Macieira-Coelho, Editor. Springer Verlag, Berlin, Heidelberg, New York (2007), ISBN 3-540-69160-0