The centrosome and asymmetric cell division

Asymmetric stem cell division is a mechanism widely employed by the cell to maintain tissue homeostasis, resulting in the production of one stem cell and one differentiating cell. However, asymmetric cell division is not limited to stem cells and is widely observed even in unicellular organisms as well as in cells that make up highly complex tissues. In asymmetric cell division, cells must organize their intracellular components along the axis of asymmetry (sometimes in the context of extracellular architecture). Recent studies have described cell asymmetry in many cell types and in many cases such asymmetry involves the centrosome (or spindle pole body in yeast) as the center of cytoskeleton organization. In this review, I summarize recent discoveries in cellular polarity that lead to an asymmetric outcome, with a focus on centrosome function.Key words: stem cell, asymmetric division, niche, centrosome, spindle orientation     

Mechanisms of asymmetric stem cell division

Stem cells self-renew but also give rise to daughter cells that are committed to lineage-specific differentiation. To achieve this remarkable task, they can undergo an intrinsically asymmetric cell division whereby they segregate cell fate determinants into only one of the two daughter cells. Alternatively, they can orient their division plane so that only one of the two daughter cells maintains contact with the niche and stem cell identity. These distinct pathways have been elucidated mostly in Drosophila. Although the molecules involved are highly conserved in vertebrates, the way they act is tissue specific and sometimes very different from invertebrates.     

G protein signaling and asymmetric cell division.

Asymmetric cell division depends on the polarization of the dividing cell for the correct alignment of the mitotic spindle and the localization of cytoplasmic determinants. Receptor-independent activation of heterotrimeric G proteins by the Drosophila GoLoco protein Partner of Inscuteable seems to represent a novel mechanism to control these events.     

Symmetric and asymmetric cell division in rat corneal epithelium

Abstract. Mitotic cells in normal, mature rat corneal epithelium were examined with a light microscope on serial, semi-thick plastic sections.
Classification of mitotic figures into horizontally, obliquely or vertically positioned with reference to the epithelial basal lamina has shown that no single configuration predominates. A striking correlation between the position of the daughter cells after cytokinesis and their morphology has been observed. Horizontal cytokinetic pairs were morphologically symmetric but vertical ones were asymmetric, displaying distinct differences between daughter cells. Analysis of earlier mitotic phases has shown that the asymmetry could also be observed in vertical anaphases and telophases.
The data provide clear morphological evidence for real asymmetric (unequal) cell division in a replacing epithelium in an adult mammal. It is concluded that asymmetric cell division in the corneal epithelium coexists with, and is as frequent as symmetric (equal) cell division. Randomness of mitotic spindle positioning implies that diverse forms of cell transfer from the proliferative into the differentiative epithelial compartments must operate. Therefore, the universality of the general model of cell renewal in stratified epithelia, which assumes a strong predominance of horizontal mitoses, exclusively equal mitotic divisions and one form of cell transfer, is questioned.     

Cell polarity and the mechanism of asymmetric cell division

During development one mechanism for generating different cell types is asymmetric cell division, by which a cell divides and contributes different factors to each of its daughter cells. Asymmetric cell division occurs through out the eukaryotic kingdom, from yeast to humans. Many asymmetric cell divisions occur in a defined orientation. This implies a cellular mechanism for sensing direction, which must ultimately lead to differences in gene expression between two daughter cells. In this review, we describe two classes of molecules: regulatory factors that are differentially expressed upon asymmetric cell division, and components of a signal transduction pathway that may define cell polarity. The lin-11 and mec-3 genes of C. elegans, the Isl-1 gene of mammals and the HO gene of yeast, encode regulatory factors that determine cell type of one daughter after asymmetric cell division. The CDC24 and CDC42 genes of yeast affect both bud positioning and orientation of mating projections, and thus may define a general cellular polarity. We speculate that molecules such as Cdc24 and Cdc42 may regulate expression of genes such as lin-11, mec-3, Isl-1 and HO upon asymmetric cell division.     

Symmetric and asymmetric cell division in rat corneal epithelium

Mitotic cells in normal, mature rat corneal epithelium were examined with a light microscope on serial, semi-thick plastic sections. Classification of mitotic figures into horizontally, obliquely or vertically positioned with reference to the epithelial basal lamina has shown that no single configuration predominates. A striking correlation between the position of the daughter cells after cytokinesis and their morphology has been observed. Horizontal cytokinetic pairs were morphologically symmetric but vertical ones were asymmetric, displaying distinct differences between daughter cells. Analysis of earlier mitotic phases has shown that the asymmetry could also be observed in vertical anaphases and telophases. The data provide clear morphological evidence for real asymmetric (unequal) cell division in a replacing epithelium in an adult mammal. It is concluded that asymmetric cell division in the corneal epithelium coexists with, and is as frequent as symmetric (equal) cell division. Randomness of mitotic spindle positioning implies that diverse forms of cell transfer from the proliferative into the differentiative epithelial compartments must operate. Therefore, the universality of the general model of cell renewal in stratified epithelia, which assumes a strong predominance of horizontal mitoses, exclusively equal mitotic divisions and one form of cell transfer, is questioned.     

Regulation of asymmetric cell division in the epidermis

For proper tissue morphogenesis, cell divisions and cell fate decisions must be tightly and coordinately regulated. One elegant way to accomplish this is to couple them with asymmetric cell divisions. Progenitor cells in the developing epidermis undergo both symmetric and asymmetric cell divisions to balance surface area growth with the generation of differentiated cell layers. Here we review the molecular machinery implicated in controlling asymmetric cell division. In addition, we discuss the ability of epidermal progenitors to choose between symmetric and asymmetric divisions and the key regulatory points that control this decision.     

Myosin-II puts the squeeze on asymmetric cell division

Asymmetric cell division--where two dissimilar daughter cells are produced--relies on asymmetric positioning of the telophase spindle midzone, which specifies the cleavage furrow. Ou et al. (2010) now report in Science a mechanism of asymmetric midzone positioning driven by a polarized cortical distribution of the contractile motor myosin-II.     

Increased asymmetric and multi-daughter cell division in mechanically confined microenvironments

As the microenvironment of a cell changes, associated mechanical cues may lead to changes in biochemical signaling and inherently mechanical processes such as mitosis. Here we explore the effects of confined mechanical environments on cellular responses during mitosis. Previously, effects of mechanical confinement have been difficult to optically observe in three-dimensional and in vivo systems. To address this challenge, we present a novel microfluidic perfusion culture system that allows controllable variation in the level of confinement in a single axis allowing observation of cell growth and division at the single-cell level. The device is capable of creating precise confinement conditions in the vertical direction varying from high (3 μm) to low (7 μm) confinement while also varying the substrate stiffness (E = 130 kPa and 1 MPa). The Human cervical carcinoma (HeLa) model with a known 3N+ karyotype was used for this study. For this cell line, we observe that mechanically confined cell cycles resulted in stressed cell divisions: (i) delayed mitosis, (ii) multi- daughter mitosis events (from 3 up to 5 daughter cells), (iii) unevenly sized daughter cells, and (iv) induction of cell death. In the highest confined conditions, the frequency of divisions producing more than two progeny was increased an astounding 50-fold from unconfined environments, representing about one half of all successful mitotic events. Notably, the majority of daughter cells resulting from multipolar divisions were viable after cytokinesis and, perhaps suggesting another regulatory checkpoint in the cell cycle, were in some cases observed to re-fuse with neighboring cells post-cytokinesis. The higher instances of abnormal mitosis that we report in confined mechanically stiff spaces, may lead to increased rates of abnormal, viable, cells in the population. This work provides support to a hypothesis that environmental mechanical cues influences structural mechanisms of mitosis such as geometric orientation of the mitotic plane or planes.     

Interdependence of filamentous actin and microtubules for asymmetric cell division

Asymmetric cell divisions are crucial to the generation of cell fate diversity. They contribute to unequal distribution of cellular factors to the daughter cells. Asymmetric divisions are characterized by a 90 degrees rotation of the mitotic spindle. There is increasing evidence that a tight cooperation between cortical, filamentous actin and astral microtubules is indispensable for successful spindle rotation. Over the past years, the dynactin complex has emerged as a key candidate to mediate actin/microtubule interaction at the cortex. This review discusses our current understanding of how spindle rotation is accomplished by the interplay of filamentous actin and microtubules in a variety of experimental systems.     

Effects of asymmetric division on a stochastic model of the cell division cycle

The stochastic model of cell division formulated by Alt and Tyson is generalized to the case of imprecise binary fission. Closed-form expressions are derived for the generation-time distribution, the birth-size and division-size distributions, the beta curve, and the correlation coefficient of generation times of sister cells. The theoretical results are compared to observations of cell division statistics in a culture of fission yeast.     

Embryonic polarity: protein stability in asymmetric cell division

Recent work on pattern formation in Caenorhabditis elegans has uncovered a new mechanism of asymmetric cell division: the cytoplasm is polarized by cortical proteins, and this polarization then influences the stability of other maternally expressed proteins that in turn determine early embryonic cell fates.     

Stem cell self-renewal: The role of asymmetric division

Asymmetric division occurs widely in different groups of organisms from single-celled to insects, mammals, and plants. The operation of asymmetrical division may differ widely in different organisms. In multicellular organisms, asymmetrical division is one of the essential features of stem cell biology. The data obtained assume one of the main biological functions of asymmetrical division to be maintenance of cell viability, beginning with stem cells. Cells continuously accumulate toxic inclusions, which are formed by damaged proteins which cannot be degraded by proteasomes. As a result of asymmetric division, these inclusions segregate into one of the daughter cells providing the ability of long-lived proliferation to another cell.     

Quantitative analysis of protein dynamics during asymmetric cell division

In dividing Drosophila sensory organ precursor (SOP) cells, the fate determinant Numb and its associated adaptor protein Pon localize asymmetrically and segregate into the anterior daughter cell, where Numb influences cell fate by repressing Notch signaling. Asymmetric localization of both proteins requires the protein kinase aPKC and its substrate Lethal (2) giant larvae (Lgl). Because both Numb and Pon localization require actin and myosin, lateral transport along the cell cortex has been proposed as a possible mechanism for their asymmetric distribution. Here, we use quantitative live analysis of GFP-Pon and Numb-GFP fluorescence and fluorescence recovery after photobleaching (FRAP) to characterize the dynamics of Numb and Pon localization during SOP division. We demonstrate that Numb and Pon rapidly exchange between a cytoplasmic pool and the cell cortex and that preferential recruitment from the cytoplasm is responsible for their asymmetric distribution during mitosis. Expression of a constitutively active form of aPKC impairs membrane recruitment of GFP-Pon. This defect can be rescued by coexpression of nonphosphorylatable Lgl, indicating that Lgl is the main target of aPKC. We propose that a high-affinity binding site is asymmetrically distributed by aPKC and Lgl and is responsible for asymmetric localization of cell-fate determinants during mitosis.     

Control of asymmetric cell division of mammalian neural progenitors

Although the vertebrate brain commonly stems from the neuroepithelial tube, the size and complexity of the pseudostratified organization of the brain have drastically expanded during mammalian evolution, resulting in the formation of a highly folded cortex. Developmental controls of neural progenitor divisions underlie these events. In this review, we introduce recent progress in understanding the control of proliferation and differentiation of neural progenitors from a structural point of view. We particularly shed light on the roles of epithelial structure and mitotic spindle orientation in the generation of various types of neural progenitors.