When fate follows age: unequal centrosomes in asymmetric cell division

A strong correlation between centrosome age and fate has been reported in some stem cells and progenitors that divide asymmetrically. In some cases, such stereotyped centrosome behaviour is essential to endow stemness to only one of the two daughters, whereas in other cases causality is still uncertain. Here, we present the different cell types in which correlated centrosome age and fate has been documented, review current knowledge on the underlying molecular mechanisms and discuss possible functional implications of this process.     

A role for a novel centrosome cycle in asymmetric cell division

Tissue stem cells play a key role in tissue maintenance. Drosophila melanogaster central brain neuroblasts are excellent models for stem cell asymmetric division. Earlier work showed that their mitotic spindle orientation is established before spindle formation. We investigated the mechanism by which this occurs, revealing a novel centrosome cycle. In interphase, the two centrioles separate, but only one is active, retaining pericentriolar material and forming a "dominant centrosome." This centrosome acts as a microtubule organizing center (MTOC) and remains stationary, forming one pole of the future spindle. The second centriole is inactive and moves to the opposite side of the cell before being activated as a centrosome/MTOC. This is accompanied by asymmetric localization of Polo kinase, a key centrosome regulator. Disruption of centrosomes disrupts the high fidelity of asymmetric division. We propose a two-step mechanism to ensure faithful spindle positioning: the novel centrosome cycle produces a single interphase MTOC, coarsely aligning the spindle, and spindle-cortex interactions refine this alignment.     

Cosegregation of asymmetric features during cell division

Cellular asymmetry plays a major role in the ageing and evolution of multicellular organisms. However, it remains unknown how the cell distinguishes ‘old’ from ‘new’ and whether asymmetry is an attribute of highly specialized cells or a feature inherent in all cells. Here, we investigate the segregation of three asymmetric features: old and new DNA, the spindle pole body (SPB, the centrosome analogue) and the old and new cell ends, using a simple unicellular eukaryote, Schizosaccharomyces pombe. To our knowledge, this is the first study exploring three asymmetric features in the same cells. We show that of the three chromosomes of S. pombe, chromosome I containing the new parental strand, preferentially segregated to the cells inheriting the old cell end. Furthermore, the new SPB also preferentially segregated to the cells inheriting the old end. Our results suggest that the ability to distinguish ‘old’ from ‘new’ and to segregate DNA asymmetrically are inherent features even in simple unicellular eukaryotes.     

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.     

Asymmetric cell division during T cell development controls downstream fate

During mammalian T cell development, the requirement for expansion of many individual T cell clones, rather than merely expansion of the entire T cell population, suggests a possible role for asymmetric cell division (ACD). We show that ACD of developing T cells controls cell fate through differential inheritance of cell fate determinants Numb and α-Adaptin. ACD occurs specifically during the β-selection stage of T cell development, and subsequent divisions are predominantly symmetric. ACD is controlled by interaction with stromal cells and chemokine receptor signaling and uses a conserved network of polarity regulators. The disruption of polarity by deletion of the polarity regulator, Scribble, or the altered inheritance of fate determinants impacts subsequent fate decisions to influence the numbers of DN4 cells arising after the β-selection checkpoint. These findings indicate that ACD enables the thymic microenvironment to orchestrate fate decisions related to differentiation and self-renewal.     

Lessons from development: A role for asymmetric stem cell division in cancer

Asymmetric stem cell division has emerged as a major regulatory mechanism for physiologic control of stem cell numbers. Reinvigoration of the cancer stem cell theory suggests that tumorigenesis may be regulated by maintaining the balance between asymmetric and symmetric cell division. Therefore, mutations affecting this balance could result in aberrant expansion of stem cells. Although a number of molecules have been implicated in regulation of asymmetric stem cell division, here, we highlight known tumor suppressors with established roles in this process. While a subset of these tumor suppressors were originally defined in developmental contexts, recent investigations reveal they are also lost or mutated in human cancers. Mutations in tumor suppressors involved in asymmetric stem cell division provide mechanisms by which cancer stem cells can hyperproliferate and offer an intriguing new focus for understanding cancer biology. Our discussion of this emerging research area derives insight from a frontier area of basic science and links these discoveries to human tumorigenesis. This highlights an important new focus for understanding the mechanism underlying expansion of cancer stem cells in driving tumorigenesis.     

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.     

Patterns of cell division and expression of asymmetric cell fate determinants in postembryonic neuroblast lineages of Drosophila

We have studied the division of postembryonic neuroblasts (Nbs) in the outer proliferation center (OPC) and central brain anlagen of Drosophila. We focused our attention on three aspects of these processes: the pattern of cellular division, the topological orientation of those divisions, and the expression of asymmetric cell fate determinants. Although larval Nbs are of embryonic origin, our results indicate that their properties appear to be modified during development. Several conclusions can be summarized: (i) In early larvae, Nbs divide symmetrically to give rise to two Nbs while in the late larval brain most Nbs divide asymmetrically to bud off an intermediate ganglion mother cell (GMC) that very rapidly divides into two ganglion cells (GC). (ii) Symmetric and asymmetric divisions of OPC Nbs show tangential and radial orientations, respectively. (iii) This change in the pattern of division correlates with the expression of inscuteable, which is apically localized only in asymmetric divisions. (iv) The spindle of asymmetrically dividing Nb is always oriented on an apical-basal axis. (v) Prospero does not colocalize with Miranda in the cortical crescent of mitotic Nbs. (vi) Prospero is transiently expressed in one of the two sibling GCs generated by the division of GMCs. The implications of these results on cell fate specification and differentiation of adult brain neurons are discussed.     

A novel transmembrane protein recruits numb to the plasma membrane during asymmetric cell division

Numb, an evolutionarily conserved cell fate-determining factor, plays a pivotal role in the development of Drosophila and vertebrate nervous systems. Despite lacking a transmembrane segment, Numb is associated with the cell membrane during the asymmetric cell division of Drosophila neural precursor cells and is selectively partitioned to one of the two progeny cells from a binary cell division. Numb contains an N-terminal phosphotyrosine-binding (PTB) domain that is essential for both the asymmetric localization and the fate specification function of Numb. We report here the isolation and characterization of a novel PTB domain-binding protein, NIP (Numb-interacting protein). NIP is a multipass transmembrane protein that contains two PTB domain-binding, NXXF motifs required for the interaction with Numb. In dividing Drosophila neuroblasts, NIP is colocalized to the cell membrane with Numb in a basal cortical crescent. Expression of NIP in Cos-7 cells recruited Numb from the cytosol to the plasma membrane. This recruitment of Numb to membrane by NIP was dependent on the presence of at least one NXXF site. In Drosophila Schneider 2 cells, NIP and Numb were colocalized at the plasma membrane. Inhibition of NIP expression by RNA interference released Numb to the cytosol. These results suggest that a direct protein-protein interaction between NIP and Numb is necessary and sufficient for the recruitment of Numb to the plasma membrane. Recruitment of Numb to a basal cortical crescent in a dividing neuroblast is essential for Numb to function as an intrinsic cell fate determinant.     

Asymmetric cell division and cell fate in plants

A variety of approaches has recently been employed to investigate how sister cells adopt distinct fates following asymmetric divisions during plant development. Surgical and drug studies have been used to analyze asymmetric divisions during both early embryogenesis in brown algae and pollen development in tobacco. Genetic screens have been used to identify genes in Arabidopsis thaliana that are required for specific asymmetric cell divisions during pollen and root development. These studies indicate that cell polarity and division orientation are closely tied to the process of cell fate specification, and suggest that differential inheritance of determinants and positional information may both be involved in the specification of cell fates following asymmetric cell division.