Despite recent progress in the identification of genes that regulate longevity, aging remains a mysterious process. One influential hypothesis is the idea that the potential for cell division and replacement are important factors in aging. In this work, we review and discuss this perspective in the context of interventions in mammals that appear to accelerate or retard aging. Rather than focus on molecular mechanisms, we interpret results from an integrative biology perspective of how gene products affect cellular functions, (...) which in turn impact on tissues and organisms. We review evidence suggesting that mutations that give rise to features resembling premature aging tend to be associated with cellular phenotypes such as increased apoptosis or premature replicative senescence. In contrast, many interventions in mice that extend lifespan and might delay aging, including caloric restriction, tend to either hinder apoptosis or result in smaller animals and thus may be the product of fewer cell divisions. Therefore, it appears plausible that changes in the number of times that cells, and particularly stem cells, divide during an organism's lifespan influence longevity and aging. We discuss possible mechanisms related to this hypothesis and propose experimental paradigms. BioEssays 30:567–578, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

During embryogenesis, cell division must be spatially and temporally regulated with respect to other developmental processes. Leech embryos undergo a series of unequal and asynchronous cleavages to produce individually recognizable cells whose lineages, developmental fates and cell cycle properties have been characterized. Thus, leech embryos provide an opportunity to examine the regulation of cell division at the level of individual well‐characterized cells within a community of different types of cells. Isolation of leech homologues of some (...) of the highly conserved regulators of the cell division cycle, and characterization of their patterns of maternal and zygotic expression, indicate that the cell divisions of early leech embryos are regulated by cell type‐specific mechanisms. These studies with leech embryos contribute to the emerging appreciation of the diverse mechanisms by which animals regulate cell division during early development. (shrink)

Cells in the basal metazoan phylum Cnidaria are characterized by remarkable plasticity in their differentiation capacity. The mechanism controlling asymmetric cell divisions is not understood in cnidarians or in any other animal group. PIWI proteins recently have been shown to be involved in maintaining the self‐renewal capacity of stem cells in organisms as diverse as ciliates, flies, worms and mammals. Seipel et al.1 find that, in the cnidarian Podocoryne carnea, the Piwi homolog Cniwi is transcriptionally upregulated when the polyp (...) generates buds, which will develop into medusae. Since transdifferentiation of striated muscle cells to smooth muscle cells also activated Cniwi expression, Cniwi appears to play a crucial role in differentiation events. The discovery should facilitate elucidation of the poorly understood factors that control asymmetric cell divisions at the beginning of animal evolution. BioEssays 26:929–931, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

The segregation of damaged components at cell division determines the survival and aging of cells. In cells that divide asymmetrically, such as Saccharomyces cerevisiae, aggregated proteins are retained by the mother cell. Yet, where and how aggregation occurs is not known. Recent work by Zhou and collaborators shows that the birth of protein aggregates, under specific stress conditions, requires active translation, and occurs mainly at the endoplasmic reticulum. Later, aggregates move to the mitochondrial surface through fis1‐dependent association. (...) During replicative aging, aggregate association with the mother‐cell mitochondria contributes to the asymmetric segregation of aggregates, because mitochondria in the daughter cell do not carry aggregates. With increasing age of mother cells, aggregates lose their connection to the mitochondria, and segregation is less asymmetric. Relating these findings to other mechanisms of aggregate segregation in different organisms, we postulate that fusion between aggregates and their tethering to organelles such as the vacuole, nucleus, ER, or mitochondria are common principles that establish asymmetric segregation during stress resistance and aging. (shrink)

Diatoms are important protists that generate one fifth of the oxygen produced annually on earth. These aquatic organisms likely derived from a secondary endosymbiosis event, and they display peculiar genomic and structural features that reflect their chimeric origin. Diatoms were one of the first models of cell division and these early studies revealed a range of interesting features including a unique acentriolar microtubule‐organising centre. Unfortunately, almost nothing is known at the molecular level, in contrast to the advances in (...) other experimental organisms. Recently the full genome sequences of two diatoms have been annotated and molecular tools have been developed. These resources offer new possibilities to re‐investigate the mechanisms of cell division in diatoms by recruiting information from more intensively studied organisms. A renaissance of the topic is further justified by the current interest in diatoms as a source of biofuels and for understanding massive diatom proliferation events in response to environmental stimuli. (shrink)

Early embryogenesis is marked by a frail Spindle Assembly Checkpoint (SAC). The time of SAC acquisition varies depending on the species, cell size or a yet to be uncovered developmental timer. This means that for a specific number of divisions, biorientation of sister chromatids occurs unsupervised. When error‐prone segregation is an issue, an aneuploidy‐selective apoptosis system can come into play to eliminate chromosomally unbalanced cells resulting in healthy newborns. However, aneuploidy content can be too great to overcome, endangering viability.SAC (...) generates a diffusible signal to lengthen time spent in mitosis if needed, ensuring correct chromosome segregation, a fundamental factor in the generation of euploid cells. Thus, it remains puzzling what benefit could come from delaying SAC acquisition till later in the development. In this review, we describe what is known on SAC acquisition in distinct species and highlight pending research as well as potential applications for such knowledge. (shrink)

Asymmetric cell division generates cell diversity and contributes to cellular aging and rejuvenation. Here, we review the molecular mechanisms enabling budding yeast to recognize spindle pole bodies (SPB, centrosome equivalent) based on their age, and guide their non‐random mitotic segregation: SPB inheritance requires the distinction of old from new SPBs and is regulated by the SPB‐inheritance network (SPIN) and the mitotic exit network (MEN). The SPIN marks the pre‐existing SPB as old and the MEN recognizes these marks (...) translating them into spindle orientation. We next revisit other molecules and structures that partition depending on their age rather than their abundance at mitosis as, for example, DNA, centrosomes, mitochondria, and histones in yeast and other systems. The recurrence of this differential behavior suggests a functional significance for numerous cell types, which we then discuss. We conclude that non‐random segregation may facilitate asymmetric cell fate determination and thereby indirectly aging and rejuvenation. (shrink)

Asymmetric cell division generates two cells that contain different regulatory proteins and express different fates. In an example of asymmetric cell division from B. subtilis, a site on the membrane of the dividing cell is chosen to establish the initial asymmetry. Recent results(1,2) show that a key regulatory protein, SpollE, is localized to one side of a sporulating B. subtilis cell, and subsequently functions in an asymmetric manner. SpollE is a phosphatase at the beginning (...) of a regulatory cascade that leads to activation of a cell fate‐determining transcription factor in only one daughter cell. (shrink)

The developmental programs of eukaryotic organisms involve the programmed transcription of genes. A characteristic gene expression pattern is established and preserved in each different cell type. Therefore, gene activation at a particular time and its maintenance during cell division are significant for cellular differentiation and individual development. Although many studies have sought to explain the molecular mechanisms of gene expression regulation, the mechanism through which gene expression states are inherited during cell division has not been (...) fully elucidated yet. This review illustrates the general principles and the complexities involved in the establishment and maintenance of active transcription through cell cycles. It focuses on the most‐recent findings about the ways in which molecular memory marks for active transcription are coordinated with cell cycle events, such as replication, mitosis and nuclear organization, to mediate transcription memory across cell division events, which may establish a unifying memory process of active transcription. BioEssays 27:1239–1245, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Graphical AbstractTo metastasize, cancer cells must be able to complete cell division in environments very different from their tissue of origin. We suggest that mitotic cell rounding, aided by several actin-regulatory oncogenes, may facilitate this process in a robust, context-independent manner.

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. (shrink)

Cell‐wall‐less bacterial variants, or L‐forms, have been described in many bacterial species under laboratory conditions, in infected eukaryotic cell cultures and inside animals. Of special interest for human health is the formation of L‐forms as a consequence of specific antibiotic treatments, and the potential involvement of L‐forms in persistent and relapsing infections. An old enigma about L‐forms is how they can divide in the absence of cell wall synthesis, since septum formation is an essential requisite for (...) class='Hi'>cell division. However, the classical definition of L‐forms as cell‐wall‐less bacterial variants may need a revision to accomodate recent observations by Richard d'Ari and coworkers:1 genetic and biochemical evidence indicates that E. coli L‐forms induced by β‐lactam antibiotics do contain small amounts of peptidoglycan, essential for their growth and probably required for septum formation. If these observations are extrapolated to all known L‐forms, the very concept of cell‐wall‐less bacteria may need revision, and be restricted to mycoplasmas and their relatives. BioEssays 29:1189–1191, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

The finely tuned mechanisms that control cell cycle progression go awry in cancer, pointing to proto‐oncogene products as important players in cell‐cycle regulation. One such proto‐oncoprotein, c‐Src, has previously been directly implicated, based on its requirement for growth factor‐stimulated DNA synthesis. Roche et al.(1) have now shown that c‐Src or its close relatives are also required for cell division to occur. The demonstration of essential functions for the Src family at multiple points in the cell (...) cycle raises important questions about the normal and transforming activities of these and other proto‐oncoproteins. (shrink)

It has been recently demonstrated that yeast cells are able to partially regress chromosome segregation in telophase as a response to DNA double‐strand breaks (DSBs), likely to find a donor sequence for homology‐directed repair (HDR). This regression challenges the traditional concept that establishes anaphase events as irreversible, hence opening a new field of research in cell biology. Here, the nature of this new behavior in yeast is summarized and the underlying mechanisms are speculated about. It is also discussed whether (...) it can be reproduced in other eukaryotes. Overall, this work brings forwards the need of understanding how cells attempt to repair DSBs when transiting the latest stages of mitosis, i.e., anaphase and telophase. (shrink)

The studies on the cAMP‐requiring mutants and their suppressors in the yeast, Saccharomyces cerevisiae, revealed that cAMP‐dependent protein phosphorylation is involved in the G1 phase of the cell cycle, in conjugation, and in the post‐meiotic stage of sporulation, and that inhibition of cAMP‐dependent protein phosphorylation is required to induce meiotic division.

Balancing self‐renewal and differentiation of stem cells is an important issue in stem cell and cancer biology. Recently, the Drosophila neuroblast (NB), neural stem cell has emerged as an excellent model for stem cell self‐renewal and tumorigenesis. It is of great interest to understand how defects in the asymmetric division of neural stem cells lead to tumor formation. Here, we review recent advances in asymmetric division and the self‐renewal control of Drosophila NBs. We summarize molecular (...) mechanisms of asymmetric cell division and discuss how the defects in asymmetric division lead to tumor formation. Gain‐of‐function or loss‐of‐function of various proteins in the asymmetric machinery can drive NB overgrowth and tumor formation. These proteins control either the asymmetric protein localization or mitotic spindle orientation of NBs. We also discuss other mechanisms of brain tumor suppression that are beyond the control of asymmetric division. (shrink)

Division of labour is a marked feature of multicellular organisms. Margulis proposed that the ancestors of metazoans had only one microtubule organizing center (MTOC), so they could not move and divide simultaneously. Selection for simultaneous movement and cell division had driven the division of labour between cells. However, no evidence or explanation for this assumption was provided. Why could the unicellular ancetors not have multiple MTOCs? The gain and loss of three possible strategies are discussed. It (...) was found that the advantage of one or two MTOC per cell is environment-dependent. Unicellular organisms with only one MTOC per cell are favored only in resource-limited environments without strong predatory pressure. If division of labour occurring in a bicellular organism just makes simultaneous movement and cell division possible, the possibility of its fixation by natural selection is very low because a somatic cell performing the function of an MTOC is obviously wasting resources. Evolutionary biologists should search for other selective forces for division of labour in cells. (shrink)

During balanced growth of cells in culture all extensive properties of the culture — e.g. cell number, total mass, total DNA content — increase exponentially at the same specific growth rate. Therefore, in some average sense, each component of a cell must double between birth and division. For DNA there exists an elaborate mechanism to ensure precise replication of the genetic material and accurate partitioning of identical copies of the genome to the two daughter cells. Do cells (...) possess another mechanism that intentionally relates the timing of cell division to overall increase in cell size, or is the coordination of growth and division an incidental consequence of size‐independent rules for progress through the cell cycle?. (shrink)

Imagine cells that live in a high‐gradient magnetic field (HGMF). Through what mechanisms do the cells sense a non‐uniform magnetic field and how such a field changes the cell fate? We show that magnetic forces generated by HGMFs can be comparable to intracellular forces and therefore may be capable of altering the functionality of an individual cell and tissues in unprecedented ways. We identify the cellular effectors of such fields and propose novel routes in cell biology predicting (...) new biological effects such as magnetic control of cell‐to‐cell communication and vesicle transport, magnetic control of intracellular ROS levels, magnetically induced differentiation of stem cells, magnetically assisted cell division, or prevention of cells from dividing. On the basis of experimental facts and theoretical modeling we reveal timescales of cellular responses to high‐gradient magnetic fields and suggest an explicit dependence of the cell response time on the magnitude of the magnetic field gradient. (shrink)

The cell division and differentiation events that occur during the development of the nematode Caenorhabditis elegans are nearly identical between different individuals, a feature that distinguishes this organism from larger and more complex metazoans, such as humans and Drosophila. In view of this discrepancy, it might be expected that the regulation of cell growth, division and differentiation in C. elegans would involve mechanisms separate from those utilized in larger animals. However, the results of recent genetic, molecular (...) and cellular studies indicate that C. elegans employs an arsenal of developmental regulatory mechanisms quite similar to those wielded by its arthropod and vertebrate relatives. Thus, the nematode system is providing both novel and complementary insights into the general problem of how growth and patterning events are integrated in development. This review offers a general perspective on the regulation of cell division and growth in C. elegans, emphasizing recent studies of these crucial aspects of development. BioEssays 24:38–53, 2002. © 2002 John Wiley & Sons, Inc. (shrink)

Focal adhesions disassemble during mitosis, but surprisingly little is known about how these structures respond to other phases of the cell cycle. Three recent papers reveal unexpected results as they examine adhesions through the cell cycle. A biphasic response is detected where focal adhesions grow during S phase before disassembly begins early in G2. In M phase, activated integrins at the tips of retraction fibers anchor mitotic cells, but these adhesions lack the defining components of focal adhesions, such (...) as talin, paxillin, and zyxin. Re‐examining cell‐matrix adhesion reveals reticular adhesions, a new class of adhesion. These αVβ5 integrin‐mediated adhesions also lack conventional focal adhesion components and anchor mitotic cells to the extracellular matrix. As reviewed here, these studies present insight into how adhesion complexes vary through the cell cycle, and how unconventional adhesions maintain attachment during mitosis while providing spatial memory to guide daughter cell re‐spreading after cell division. (shrink)

The secondary vascular tissues (xylem and phloem) of woody plants originate from a vascular cambium and develop as radially oriented files of cells. The secondary phloem is composed of three or four cell types, which are organised into characteristic recurrent cellular sequences within the radial cell files of this tissue. There is a gradient of auxin (indole acetic acid) across both the cambium and the immediately postmitotic cells within the xylem and phloem domains, and it is believed that (...) this morphogen, probably in concert with other morphogenic factors, is closely associated with the determination and differentiation of the different cells types in each tissue. A hypothesis is developed that, in conjunction with the positional values conferred by the graded radial distribution of morphogen, cell divisions at particular positions within the cambium are sufficient to determine not only each of the phloem cell types but also their recurrent pattern of differentiation within each radial cell file. BioEssays 27: 533–541, 2005. © 2005 Wiley periodicals, Inc. (shrink)

In the rod‐shaped cells of E. coli, chromosome segregation takes place immediately after replication has been completed. A septum then forms between the two sister chromosomes. In the absence of certain membrane proteins, cells grow instead as large, multichromosomal spheres that divide successively in planes that are at right angles to one another. Although multichromosomal, the spherical cells cannot be maintained as heterozygotes. These observations imply that, in these mutants, each individual chromosome gives rise to a separate clone of descendant (...) cells. This suggests a model in which sites for cell division form between pairs of sister chromosomes at the time of segregation, but are not used in spherical cells until further rounds of replication have taken place, thus ensuring clonal (‘hierarchical’) segregation of chromosomes into progeny cells. The role of the morphogenetic membrane proteins is to convert the basically spherical cell into a cylinder that is able to divide as soon as replication and segregation have been completed, and thus to maximise the number of viable cells per genome. (shrink)

Multicellular organisms develop on a predictable schedule that depends on both cell‐intrinsic timers and sequential cell‐cell interactions mediated by extracellular signals. The interplay between intracellular timers and extracellular signals is well illustrated by the development of oligodendrocytes, the cells that make the myelin in the vertebrate central nervous system. An intrinsic timing mechanism operates in each oligodendrocyte precursor cell to limit the length of time the cell divides before terminally differentiating. This mechanism consists of two (...) components, a timing component, which depends on the mitogen platelet‐derived growth factor (PDGF) and measures elapsed time, and an effector component, which depends on thyroid hormone and stops cell division and initiates differentiation at the appropriate time. The cell‐cycle inhibitor p27/Kip1 accumulates in the precursor cells as they proliferate and is part of both components of the timer. It seems likely that similar timing mechanisms operate in other cell lineages. BioEssays 22:64–71, 2000. ©2000 John Wiley & Sons, Inc. (shrink)

Apical cells are universally present in lower plants and their description has been mostly viewed morphologically as single-celled meristems. This study attempts to demonstrate that the roles of apical cells and more generally of meristems collectively are (a) often the proliferative source of all cells in a plant, (b) sometimes a formative centre in histogenesis and organogenesis and (c) always a regulatory site. As a proliferative centre it occurs as a series of apical cells through a mitotic lineage by unequal (...) divisions which includes a rotational pattern to form cells distributed according to the symmetry of its organ. As a formative centre it determines leaf arrangement in mosses and leafy liverworts as well as the root cap and gametophyte cushion in ferns. It appears initially to determine the type of organ and later the organ determines the type of apical cells within. As a regulatory centre it activates distal secondary cells to proliferate as well as inhibiting neighbouring cells from becoming apical cells to preserve the identity of an organ during its development.Based on these three roles by which apical cells can be recognized an argument can be drafted that seed plants may have apical cells, although morphologically indistinguishable from other cells, singularly or in batteries instead of possessing the traditionally described multicellular meristems. (shrink)

In recent years, live imaging has been adopted to study stem cells in their native environment at cellular resolution. In the skeletal muscle field, this has led to visualising the initial events of muscle repair in mouse, and the entire regenerative response in zebrafish. Here, we review recent discoveries in this field obtained from live imaging studies. Tracking of tissue resident stem cells, the satellite cells, following injury has captured the morphogenetic dynamics of stem/progenitor cells as they facilitate repair. Asymmetric (...) satellite cell division generated a clonogenic progenitor pool, providing in vivo validation for this mechanism. Furthermore, there is an emerging role of stem/progenitor cell guidance at the injury site by cellular protrusions. This review concludes that live imaging is a critical tool for discovering the distinct processes that occur during regeneration, emphasising the importance of imaging in diverse animal models to capture the entire scope of stem cell functions. (shrink)

Chromosome segregation requires the ordered separation of the newly replicated chromosomes between the two daughter cells. In most cells, this requires nuclear envelope (NE) disassembly during mitotic entry and its reformation at mitotic exit. Nuclear envelope breakdown (NEB) results in the mixture of two cellular compartments. This process is controlled through phosphorylation of multiple targets by cyclin‐dependent kinase 1 (Cdk1)‐cyclin B complexes as well as other mitotic enzymes. Experimental evidence also suggests that nucleo‐cytoplasmic transport of critical cell cycle regulators (...) such as Cdk1‐cyclin B complexes or Greatwall, a kinase responsible for the inactivation of PP2A phosphatases, plays a major role in maintaining the boost of mitotic phosphorylation thus preventing the potential mitotic collapse derived from NEB. These data suggest the relevance of nucleo‐cytoplasmic transport not only to communicate cytoplasmic and nuclear compartments during interphase, but also to prepare cells for the mixture of these two compartments during mitosis. (shrink)

Two enzymes involved in the synthesis of pyrimidine and purine nucleotides, CTP synthase (CTPS) and IMP dehydrogenase (IMPDH), can assemble into a single or very few large filaments called rods and rings (RR) or cytoophidia. Most recently, asymmetric cytoplasmic distribution of organelles during cell division has been described as a decisive event in hematopoietic stem cell fate. We propose that cytoophidia, which could be considered as membrane‐less organelles, may also be distributed asymmetrically during mammalian cell (...) class='Hi'>division as previously described for Schizosaccharomyces pombe. Furthermore, because each type of nucleotide intervenes in distinct processes (e.g., membrane synthesis, glycosylation, and G protein‐signaling), alterations in the rate of synthesis of specific nucleotide types could influence cell differentiation in multiple ways. Therefore, we hypothesize that whether a daughter cell inherits or not CTPS or IMPDH filaments determines its fate and that this asymmetric inheritance, together with the dynamic nature of these structures enables plasticity in a cell population. (shrink)

In the 4 1/2 to 5 days between fertilization and implantation, the mouse conceptus must gain the abilities to implant and produce an embryo. Each of these is the sole developmental responsibility of one of two cell types forming the blastocyst, trophectoderm and inner cell mass (ICM), respectively. Trophectoderm is a polarized transporting epithelium while the ICM is an aggregate of non‐epithelial pluripotent stem cells. These two cell types originate from the division of polar blastomeres when (...) their cleavage furrows parallel their apical surfaces. Blastomeres polarize in response to asymmetric cell–cell contact, and understanding the mechanism of this induction is regarded as the key to understanding the origin of trophectoderm and ICM. Here we propose a model based on transcellular ion current loops for the induction of cell polarity during the development of the first epithelium, trophectoderm. (shrink)

Relations occur on all levels of systems. Following a major assumption of generalized quantum theory, namely that the principles of quantum mechanics will occur on higher system levels as well, it was investigated in an a posteriori analysis of pre-existing data whether relational patterns found for two-photon experiments are similarly performed by two cell-populations. In particular, the typical pattern in outcomes of two-photon entanglement experiments was extrapolated to discover similar patterns of relationships in the cellular biological system of the (...) Ciliate Paramecium caudatum. In the former case we find one photon assuming a particular state when being measured and the other assuming a correlated state with regard to the first particle. From a perspective of degrees of freedom (df) the author interprets this outcome as follows: Each particle has only one df for assuming a particular state (e.g. its spin). When measured this is leading to a pattern: They use their two degrees of freedom for establishing a relation among them (particle-to-particle) and for a relation with the environment (particle-to-measurement). If this pattern is unique then we should find it also in cell-to-cell relationships. It was suggested to consider causations in cell-to-cell relations as the analogue to the relationship between the quantum particles (see above) and the dependence of repeating the experiments as the analogue to the measurement event in the quantum experiment. It was hypothesized that in a relational system of two cell populations only one should be sensitive to the repetition of the experiment. The other population, however, should establish a relation with the first one. Since the author had successfully performed experiments with pairs of cell populations that were separated with glass barriers from each other but having effects on each other (Fels in PLoS One 4:e5086, 2009), the system was perfectly well suited for testing the hypothesis. The assessed cell variable was cell division. An a posteriori analysis of three similar experiments confirmed that when populations were in a relation with each other, only one of them stood in relation with the repetition of the experiment. (shrink)

Polyploid cells contain multiple copies of all chromosomes. Polyploidization can be developmentally programmed to sustain tissue barrier function or to increase metabolic potential and cell size. Programmed polyploidy is normally associated with terminal differentiation and poor proliferation capacity. Conversely, non‐programmed polyploidy can give rise to cells that retain the ability to proliferate. This can fuel rapid genome rearrangements and lead to diseases like cancer. Here, the mechanisms that generate polyploidy are reviewed and the possible challenges upon polyploid cell (...) division are discussed. The discussion is framed around a recent study showing that asynchronous cell cycle progression (an event that is named “chronocrisis”) of different nuclei from a polyploid cell can generate DNA damage at mitotic entry. The potential mechanisms explaining how mitosis in non‐programmed polyploid cells can generate abnormal karyotypes and genetic instability are highlighted. (shrink)

Ribosomal RNA transcription was one of the first model systems for molecular characterization of a transcription regulatory mechanism and certainly one of the best studied in the widest range of organisms. In multicellular organisms, however, the issue of cell‐type‐specific regulation of rRNA transcription has not been well addressed. Here I propose that a systematic study of cell‐type‐specific regulation of rRNA transcription may reveal new regulatory mechanisms that have not been previously realized. Specifically, issues concerning the cell‐type‐specific requirement (...) for rRNA production, the universality of Pol I transcription complex and the division of rDNA into regulatory subdomains are discussed. BioEssays 28: 719–725, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Cells and tissues are continuously exposed to a changing microenvironment, hence the necessity of a flexible modulation of gene expression that in complex organism have been achieved through specialized chromatin mechanisms. Chromatin-based cell memory enables cells to maintain their identity by fixing lineage specific transcriptional programs, ensuring their faithful transmission through cell division; in particular PcG-based memory system evolved to maintain the silenced state of developmental and cell cycle genes. In evolution the complexity of this system (...) have increased, particularly in vertebrates, indicating combinatorial and dynamic properties of Polycomb proteins, in some cases even overflowing outside the cell nucleus. Therefore, their function may not be limited to the imposition of rigid states of genetic programs, but on the ability to recognize signals and allow plastic transcriptional changes in response to different stimuli. Here, we discuss the most novel PcG mediated memory functions in facing and responding to the challenges posed by a fluctuating environment. Cellular microenvironment can regularly change, hence the need for a dynamic modulation of transcriptional programs by the epigenome. In the current review, we highlight novel emerging aspects of epigenetic memory controlled by PcG proteins and the evolution of specialized functions to convey plasticity and adaptability to environmental changes. (shrink)

Tetrahymena has been used as a model cell system in many studies of morphogenesis, conjugation, gene mapping, cell division and growth kinetics. In this article, we consider some advances which have resulted from the successful development of a chemically defined medium (CDM), and how subsequent work has extended the contribution that this organism has made to our understanding of different aspects of growth, nutrition, cell cycle control, cytokinesis and intercellular signalling. Finally, we discuss the considerable potential (...) that has arisen for the biotechnological exploitation of this big and rapidly growing eukaryotic cell. (shrink)

Development of an animal embryo involves the coordination of cell divisions, a variety of inductive interactions and extensive cellular rearrangements. One of the biggest challenges in developmental biology is to explain the relationships between these processes and the mechanisms that regulate them. Teleost embryos provide an ideal subject for the study of these issues. Their optical lucidity combined with modern techniques for the marking and observation of individual living cells allow high resolution investigations of specific morphogenetic movements and the (...) construction of detailed fate maps. In this review we describe the patterns of cell divisions, cellular movements and other morphogenetic events during zebrafish early development and discuss how these events relate to the formation of restricted lineages. (shrink)

Recently, Quyn et al. demonstrated that cells within the stem cell zone of human and mouse intestinal crypts tend to align their mitotic spindles perpendicular to the basal membrane of the crypt. This is associated with asymmetric division, whereby particular proteins and individual chromatids are preferentially segregated to one daughter cell. In colonic mucosa containing a heterozygous adenomatous polyposis coli gene (APC) mutation the asymmetry is lost. Here, we discuss asymmetric stem cell division as an (...) anti‐tumourigenic mechanism. We describe how hierarchical tissue structures suppress somatic evolution, and discuss the relative merits of template strand retention to limit the accumulation of DNA replication errors. We suggest experiments to determine whether somatic mutations resulting in loss of spindle alignment confer an advantage within the stem cell niche. Finally, we discuss whether lack of spindle alignment constitutes an oncogenic event per se, with particular reference to studies in model organisms, and the timing of chromosomal instability in human cancers. (shrink)

A determined division wall positioning in each plant cell with respect to the last formed division wall leads to autoreproductive configurations which can simulate plant-like meristems as such with 2/5 phyllotactic patterns. L-map systems are used to generate the corresponding topological wall nets. But in these patterns cells are not six-sided as mostly found in layers. It is shown that wall staggering cannot be a determinate device of the cell itself, nor a randomized dissociation of the (...) cross walls, but results from a physical control with interaction between adjacent cells. It is independent of the cellular program responsible for the appearance of patterns like 2/5 phyllotaxis which is of a pentameric nature. (shrink)

Major events of the cell cycle—DNA synthesis, mitosis and cell division—are regulated by a complex network of protein interactions that control the activities of cyclin‐dependent kinases. The network can be modeled by a set of nonlinear differential equations and its behavior predicted by numerical simulation. Computer simulations are necessary for detailed quantitative comparisons between theory and experiment, but they give little insight into the qualitative dynamics of the control system and how molecular interactions determine the fundamental physiological (...) properties of cell replication. To that end, bifurcation diagrams are a useful analytical tool, providing new views of the dynamical organization of the cell cycle, the role of checkpoints in assuring the integrity of the genome, and the abnormal regulation of cell cycle events in mutants. These claims are demonstrated by an analysis of cell cycle regulation in fission yeast. BioEssays 24:1095–1109, 2002. © 2002 Wiley‐Periodicals, Inc. (shrink)

Biological development is about history, the history of an individual through time. Historically, the dominant epigenetic tradition has seen the developmental process as an unfolding of potential or in terms of the emergence of new organization that becomes an individual organism over time. The concept of development has included differentiation, growth, and morphogenesis; since the mid-nineteenth century, it has been seen in terms of cell division. Along the way have come explorations of such issues as the extent to (...) which development is driven by hereditary determination rather than flexible regulation in response to changing conditions. Some researchers have focused specifically on examining the capacity for regeneration in response to injury or loss, or on the extent to which parts are self-organizing individually rather than determined segments of a whole. This paper introduces the historical study of development. (shrink)

Centriole duplication has been an area of interest since the late 1800s when Boveri suggested that these structures were central organizers for mitosis and cell division. Two groups1, 2 have delineated a linear pathway for centriole assembly. In C. elegans, Pelletier and coworkers1 have identified intermediates in the pathway using cryo‐electron tomography. Surprising, the first intermediate is a hollow tube of 60 nm that increases in diameter and then elongates before acquiring microtubules. Similar structures have not been observed (...) to date in other centrioles. BioEssays 29:630–634, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Using as case studies two early diagrams that represent mechanisms of the cell division cycle, we aim to extend prior philosophical analyses of the roles of diagrams in scientific reasoning, and specifically their role in biological reasoning. The diagrams we discuss are, in practice, integral and indispensible elements of reasoning from experimental data about the cell division cycle to mathematical models of the cycle’s molecular mechanisms. In accordance with prior analyses, the diagrams provide functional explanations of (...) the cell cycle and facilitate the construction of mathematical models of the cell cycle. But, extending beyond those analyses, we show how diagrams facilitate the construction of mathematical models, and we argue that the diagrams permit nomological explanations of the cell cycle. We further argue that what makes diagrams integral and indispensible for explanation and model construction is their nature as locality aids: they group together information that is to be used together in a way that sentential representations do not. (shrink)

D‐amino acids are being recognized as functionally important molecules in mammals. We recently identified endogenous D‐cysteine in mammalian brain. D‐cysteine is present in neonatal brain in substantial amounts (mM) and decreases with postnatal development. D‐cysteine binds to MARCKS and a host of proteins implicated in cell division and neurodevelopmental disorders. D‐cysteine decreases phosphorylation of MARCKS in neural progenitor cells (NPCs) affecting its translocation. D‐cysteine controls NPC proliferation by inhibiting AKT signaling. Exogenous D‐cysteine inhibits AKT phosphorylation at Thr 308 (...) and Ser 473 in NPCs. D‐cysteine treatment of NPCs led to 50% reduction in phosphorylation of Foxo1 at Ser 256 and Foxo3a at Ser 253. We hypothesize that in the developing brain endogenous D‐cysteine is as a physiologic regulator of NPC proliferation by inhibiting AKT signaling mediated by Foxo1 and Foxo3a. Endogenous D‐cysteine may regulate mammalian neurodevelopment with roles in schizophrenia and Alzheimer's disease (AD). (shrink)

Microfluidic technology – the manipulation of fluids at micrometer scales – has revolutionized many areas of synthetic biology. The bottom‐up synthesis of “minimal” cell models has traditionally suffered from poor control of assembly conditions. Giant unilamellar vesicles (GUVs) are good models of living cells on account of their size and unilamellar membrane structure. In recent years, a number of microfluidic approaches for constructing GUVs has emerged. These provide control over traditionally elusive parameters of vesicular structure, such as size, lamellarity, (...) membrane composition, and internal contents. They also address sophisticated cellular functions such as division and protein synthesis. Microfluidic techniques for GUV synthesis can broadly be categorized as continuous‐flow based approaches and droplet‐based approaches. This review presents the state‐of‐the‐art of microfluidic technology, a robust platform for recapitulating complex cellular structure and function in synthetic models of biological cells. (shrink)

The three cycles of cell division immediately following theformation of the cellular blastoderm during Drosophila embryogenesis display an invariant pattern(1,2). Bursts of transcription of a gene called string are required and sufficient to trigger mitosis at this time during development(3). The activator of mitosis encoded by the string gene is a positive regulator of cdc2 kinase and a Drosophila homologue of the Saccharomyces pombe cdc25 tyrosine phosphatase(4,5). Evidence presented in a recent paper(6) demonstrates that transcription of string, and (...) hence the timing and pattern of mitosis in the postblastoderm embryo, is under complex developmental control. Several lines of evidence support this interpretation, including the analysis of string transcription in pattern formation mutants, cell cycle arrest mutants, and the preliminary characterization of an extensive cis‐acting regulatory region. (shrink)