The maintenance of cell size homeostasis has been studied for years in different cellular systems. With the focus on ‘what regulates cell size’, the question ‘why cell size needs to be maintained’ has been largely overlooked. Recent evidence indicates that animal cells exhibit nonlinear cell size dependent growth rates and mitochondrial metabolism, which are maximal in intermediate sized cells within each cell population. Increases in intracellular distances and changes in the relative (...) cell surface area impose biophysical limitations on cells, which can explain why growth and metabolic rates are maximal in a specific cell size range. Consistently, aberrant increases in cell size, for example through polyploidy, are typically disadvantageous to cellular metabolism, fitness and functionality. Accordingly, cellular hypertrophy can potentially predispose to or worsen metabolic diseases. We propose that cell size control may have emerged as a guardian of cellular fitness and metabolic activity. Cell size is intimately connected to metabolism and growth rate, which are influenced by mitochondrial activity and biophysical constraints. We discuss that cellular fitness is often cell-size dependent. While the current evidence relies largely on proliferating cells, this connection from cell size to fitness may also help explain metabolic diseases. (shrink)

Unstable Accumulating Activator models for cellular size control propose an activator that accumulates in a size-dependent manner and triggers cell cycle progression once it has reached a certain threshold. Having a short half life makes such an activator responsive to changes in cell size and makes specific predictions for how cells respond to perturbation. In particular, it explains the curious phenomenon of excess mitotic delay. Excess mitotic delay, first observed in Tetrahymena in the '50s, (...) is a phenomenon in which a pulse of protein synthesis inhibition causes a delay in mitotic entry that is longer than the pulse and that gets longer the later in the cell cycle the pulse is delivered. The interpretation of this phenomenon championed by Zeuthen and Mitchison in the '60s and '70s is that an unstable activator of mitosis is degraded during the pulse and has to be resynthesized to a threshold level to trigger mitosis; small cells have more time to resynthesize the activator before mitosis and so suffer less excess delay, whereas, large cells have less time thus suffer greater excess delay. Fifty years later, with our detailed understanding of cell cycle biochemistry, we can identify and test candidate Unstable Accumulating Activators. Here I review the field and further develop this concept. Excess mitotic delay, the phenomenon in which inhibition of protein synthesis causes a longer delay than the pulse of inhibition, is consistent with cell size control by an unstable accumulating activator, but not a stable activator. (shrink)

Graphical AbstractOrganelles are reaction vessels containing metabolic pathways. As in a chemical factory, the size of the reaction vessels limits the rate of product formation. Organelle size is tuned to metabolic needs, hence reprogramming organelle size could be a novel therapeutic strategy as well as a new tool for metabolic engineering.

It has generally been observed that cells grow to a certain size before they divide. In the last few years, the PI3K signal transduction pathway has emerged as one of the main signaling routes utilized by cells to control their increase in size. Here we focus on two components of this pathway, PKB and S6K, and briefly review the experiments that initially uncovered their roles in cell size control. In addition, we discuss a number (...) of recent observations suggesting that the generic models used to describe this pathway to date may have been oversimplified. Indeed, recent observations in Drosophila and mouse support a more complex interaction between these signaling components in development. Finally, we have utilized two contemporary studies involving PKB‐ and S6K‐deficient mice as a paradigm to underscore the importance of cell size and to accurately delineate the connections between signaling pathways for human disease, such as diabetes mellitus. BioEssays 24:65–71, 2002. © 2002 John Wiley & Sons, Inc. (shrink)

The Schaechter–Maaløe–Kjeldgaard papers, which have their 50th anniversary this year, have major implications for understanding the cell cycle, control of cell growth, control of cell size, metabolic control, the basic bacterial growth curve, and myriad other bacterial and eukaryotic growth phenomena. These ideas have broad applications that should be considered in current studies of the cell cycle. In particular, the emphasis on steady‐state growth conditions, and clear and sharp changes in growth conditions (...) were fundamental to their experiments and have been codified in the principles of the Copenhagen School of Microbiology. BioEssays 30:1019–1024, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Among all organisms, the size of each body part or organ scales with overall body size, a phenomenon called allometry. The study of shape and form has attracted enormous interest from biologists, but the genetic, developmental and physiological mechanisms that control allometry and the proportional growth of parts have remained elusive. Recent progress in our understanding of body‐size regulation provides a new synthetic framework for thinking about the mechanisms and the evolution of allometric scaling. In particular, (...) insulin/IGF signaling, which plays major roles in longevity, diabetes and the regulation of cell, organ and body size, might also be centrally involved in regulating organismal shape. Here we review recent advances in the fields of growth regulation and endocrinology and use them to construct a developmental model of static allometry expression in insects. This model serves as the foundation for a research program that will result in a deeper understanding of the relationship between growth and form, a question that has fascinated biologists for centuries. BioEssays 29:536–548, 2007. © 2007 Wiley Periodicals, Inc. (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)

A marked feature of eukaryotic programmed cell death is an early drop in mitochondrial transmembrane potential. This results from the opening of permeability transition pores, which are composed of adenine nucleotide translocators and mitochondrial porins. The latter share striking similarites with bacterial porins, (including down‐regulation of their pore size by purine nucleotides), suggesting a common origin. The porins of some invasive bacteria play a crucial role during their accommodation inside the host cell and this co‐existence resembles the (...) endosymbiotic origin of mitochondria. The above observations suggest that early in eukaryotic evolution, former invaders may have used porin‐type channels to enter their host and to induce its death when the levels of its cytoplasmic purine nucleotides were dropped. The appearance of adenosine nucleotide translocators in the primitive eukaryotes, which permitted usage of the oxidative metabolism of the invaders, provided the basis for the permeability transition phenomena, now linked to the apoptotic process. Bcl‐2‐type molecules, being able to modulate the permeability transition pores by interaction with adenosine nucleotide translocators, may have played an essential role in conferring a means of controlling apoptosis. (shrink)

The Drosophila Bolwig organs are small photoreceptor bundles that facilitate the phototactic behavior of the larva. Comparative literature suggests that these highly reduced visual organs share evolutionary ancestry with the adult compound eye. A recent molecular genetic study produced the first detailed account of the mechanisms controlling differential opsin expression and photoreceptor subtype determination in these enigmatic eyes of the Drosophila larva. Here, the evolutionary implications are examined, taking into account the dynamic diversification of opsin genes and the spatial regulation (...) of opsin homolog expression in other insects. It is concluded that, consistent with their common evolutionary roots, the Drosophila larval and adult eyes use the same mechanisms for the regulation of opsin expression and photoreceptor cell fate specification. Strikingly, the structurally highly derived Bolwig organs retained a more ancestral state of opsin expression and regulation. Inconspicuous in size, the Drosophila larval eyes deliver useful lessons in the reconstruction of homology between neuronal cell types with gene expression data, and on the conservative nature of gene regulatory network evolution during the emergence of novel organs from ancestral templates. BioEssays 30:980–993, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

The transparent sea urchin embryo provides a laboratory for study of morphogenesis. The calcareous endoskeleton is formed by a syncytium of mesenchyme cells in the blastocoel. The locations of mesenchyme in the blastocoel, the size of the skeleton, and even the branching pattern of the skeletal rods, are governed by interactions with the blastula wall. Now Guss and Ettensohn(1) show that the rate of deposition of CaCO3 in the skeleton is locally controlled in the mesenchymal syncytium, as is the (...) pattern of expression of three genes involved in skeleton formation. They propose that short range signals emanating from the blastula wall regulate many aspects of the biomineralization process. (shrink)

hiCLIP (RNA hybrid and individual‐nucleotide resolution ultraviolet cross‐linking and immunoprecipitation), is a novel technique developed by Sugimoto et al. (2015). Here, the use of different adaptors permits a controlled ligation of the two strands of a RNA duplex allowing the identification of each arm in the duplex upon sequencing. The authors chose a notoriously difficult to study double‐stranded RNA‐binding protein (dsRBP) termed Staufen1, a mammalian homolog of Drosophila Staufen involved in mRNA localization and translational control. Using hiCLIP, they discovered (...) a dominance of intramolecular RNA duplexes compared to the total RNA duplexes identified. Importantly, the authors discovered two different types of intramolecular duplexes in the cell: highly translated mRNAs with long‐range duplexes in their 3′‐UTRs and poorly translated mRNAs with duplexes in their coding region. In conclusion, the authors establish hiCLIP as an important novel technique for the identification of RNA secondary structures that serve as in vivo binding sites for dsRBPs. (shrink)

The embryonic vertebrate face is composed of similarly sized buds of neural crest‐derived mesenchyme encased in epithelium. These buds or facial prominences grow and fuse together to give the postnatal morphology characteristic of each species. Here we review the role of neural crest cells and foregut endoderm in differentiating facial features. We relate the developing facial prominences to the skeletal structure of the face and review the signals and genes that have been shown to play an important role in facial (...) morphogenesis. We also examine two experiments one at the genetic level and one at the signal level in which transformation of facial prominences and subsequent change of jaw identity was induced. We propose that signals such as retinoids and BMPs and downstream transcription factors such as Distal‐less related genes specify jaw identity. BioEssays 25:554–568, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

The development of organs during animal development requires the allocation of appropriate numbers of cells to each part of the structure. Yet in Drosophila the patterns of cell proliferation can be quite different from one individual to the next, and in fact can be altered experimentally without altering final morphology. The developing pattern seems to control proliferation, rather than the other way around. Even though the pattern of proliferation is variable, there is some order to it. A recent (...) paper(1) shows that small clusters of cells in developing cell populations are in mitotic synchrony, but that the synchrony is transient. What is the significance of this mitotic synchrony? (shrink)

Significant strides have been made in recent years towards understanding the molecular basis of cell cycle progression in the model bacterium Caulobacter crescentus. At the heart of cell cycle regulation is a multicomponent transcriptional feedback loop, governing the production of successive regulatory waves or pulses of at least three master regulatory proteins. These oscillating master regulators direct the execution of phase‐specific events and, importantly, through intrinsic genetic switches not only determine the length of a given phase, but also (...) provide the driving force that catapults the cell into the next stage of the cell cycle. The genetic switches act as fail safe mechanisms that prevent the cell cycle from relapsing and thus govern the ordered production and the periodicity of these regulatory waves. Here, we detail how the master regulators CtrA, GcrA and DnaA coordinate cell cycle progression and polar development in Caulobacter. BioEssays 28: 355–361, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Cell size is an important determinant of body size. While the genetic mechanisms of cell size regulation have been well studied in yeast, this process has only recently been addressed in multicellular organisms. One recent report by Wang et al. (2002) shows that in the nematode C. elegans, the TGFβ‐like pathway acts in the hypodermis to regulate cell size and consequently body size.1 This finding is an exciting step in discovering the molecular (...) mechanisms that control cell and body size. BioEssays 25:305–308, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

There are an increasing number of cell therapy approaches being studied and employed world‐wide. An emerging area in this field is the use of human pluripotent stem cell (hPSC) products for the treatment of injuries/diseases that cannot be effectively managed through current approaches. However, as with any cell therapy, vast numbers of functional and safe cells are required. Bioreactors provide an attractive avenue to generate clinically relevant cell numbers with decreased labour and decreased batch to batch (...) variation. Yet, current methods of performing quality control are not readily scalable to the cell densities produced during bioreactor scale‐up. One potential solution is the application of inducible/controllable suicide genes that can trigger cell death in unwanted cell types. These types of approaches have been demonstrated to increase the quality and safety of the resultant cell products. In this review, we will provide background on these approaches and how they could be used together with bioreactor technology to create effective bioprocesses for the generation of high quality and safe hPSCs for use in regenerative medicine approaches. (shrink)

The quantitative study of regulation of cell growth and proliferation began with the development of the technique for monolayer culture of vertebrate cells in the late 1960s. The basic parameters were defined in the early physiological studies, which continued through the next decade. These included specific and non-specific growth factors and the requirement for continuous exposure to such factors through most of the G1 period for progression to S. In the course of this work, the diversity of biochemical responses (...) and the critical role of increased protein synthesis and accumulation for the onset of DNA synthesis were elucidated. In particular, a central role of free cytosolic Mg2+ in direct regulation of protein synthesis and in ancillary processes as a response to membrane perturbation was established. Eventually, the physiological era was superseded by the molecular era beginning in the 1980s. This work focussed on specific receptors for growth factors that entrained a protein kinase cascade, which terminated in a higher frequency of initiation of protein synthesis. However, the molecular studies virtually ignored the key results of the physiological era. Recent studies of the penultimate molecular steps in the regulatory pathway of protein synthesis, however, have supported a model of growth regulation involving membrane perturbation and MgATP2− concentration, results that integrate the findings of the physiological and molecular eras. The resulting relatively simple “membrane, magnesium mitosis” (MMM) model of proliferation control can explain the seeming paradox of the variety of specific and non-specific growth-enhancing treatments that are mediated by the plasma membrane and which bring about a shared, complex but coordinated growth response that drives cell proliferation. BioEssays 27:311–320, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

The regulatory mechanism which ensures that eukaryotic chromosomes replicate precisely once per cell cycle is a basic and essential cellular property of eukaryotes. This fundamental aspect of DNA replication is still poorly understood, but recent advances encourage the view that we may soon have a clearer picture of how this regulation is achieved. This review will discuss in particular the role of proteins in the minichromosome maintenance (MCM) family, which may hold the key to understanding how DNA is replicated (...) once, and only once, per cell cycle. (shrink)

Size control depends on both the regulation of growth rate and the control over when to stop growing. Studies of Drosophila melanogaster have shown that insulin and Target of Rapamycin (TOR) pathways play principal roles in controlling nutrition‐dependent growth rates. A TOR‐mediated nutrient sensor in the fat body detects nutrient availability, and regulates insulin signaling in peripheral tissues, which in turn controls larval growth rates. After larvae initiate metamorphosis, growth stops. For growth to stop at the correct (...) time, larvae need to surpass a critical weight. Recently, it was found that the insulin‐dependent growth of the prothoracic gland is involved in assessing when critical weight has been reached. Furthermore, mutations in DHR4, a repressor of ecdysone signaling, reduce critical weight and adult size. Thus, the mechanisms that control growth rates converge on those assessing size to ensure that the larvae attain the appropriate size at metamorphosis. BioEssays 29:344–355, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

How size is controlled during animal development remains a fascinating problem despite decades of research. Here we review key concepts in size biology and develop our thesis that much can be learned by studying how different organ sizes are differentially scaled by homeotic selector genes. A common theme from initial studies using this approach is that morphogen pathways are modified in numerous ways by selector genes to effect size control. We integrate these results with other pathways (...) known to regulate organ size in developing a comprehensive model for organ size control. ©2007 Wiley Periodicals, Inc BioEssays 30:843–853, 2008. © 2008 Wiley Periodicals, Inc. (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)

Transplantation experiments have shown that developing metazoan organs carry intrinsic information about their size and shape. Organ and body size are also sensitive to extrinsic cues provided by the environment, such as the availability of nutrients. The genetic and molecular pathways that contribute to animal size and shape are numerous, yet how they cooperate to control growth is mysterious. The recent identification and characterization of several mutations affecting growth in Drosophila melanogaster promises to provide insights. Many (...) of these mutations affect the extrinsic control of animal size; others affect the organ‐intrinsic control of pattern and size. In this review, we summarize the characteristics of some of these mutations and their roles in growth and size control. In addition, we speculate about possible connections between the extrinsic and intrinsic pathways controlling growth and pattern. BioEssays 24:54–64, 2002. © 2002 John Wiley & Sons, Inc. (shrink)

The stable differentiation of cells into other cell types typically involves dramatic reorganization of cellular structures and functions. This often includes remodeling of the cell cycle and the apparatus that controls it. Here we review our understanding of the role and regulation of cell cycle control elements during cell differentiation in the yeast, Saccharomyces cerevisiae. Although the process of differentiation may be more overtly obvious in metazoan organisms, those systems are by nature more difficult to (...) study at a mechanistic level. We consider the relatively well‐understood mechanisms by which mating‐type switching and the pheromone‐induced differentiation of gametes are coupled to the cell cycle as well as the more obscure mechanisms that govern the remodeling of the cell cycle during meiosis and filamentous growth. In some cases, the cell cycle is a primary stimulus for differentiation whereas, in other cases, the signals that promote differentiation alter the cell cycle. Thus, despite relative simplicity of these processes in yeast, the nature of the interplay between the cell cycle and differentiation is diverse. BioEssays 25:856–867, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Integrin‐mediated cell adhesion and subsequent cell spreading are essential for the growth and survival of many cell types. While integrin engagement is known to activate various signalling pathways, the role that cell spreading plays in the control of growth and survival is not clear. Using a novel technique, however, Chen et al.(1) demonstrate that the effect of cell spreading on growth and survival is not a consequence of increased area of contact with the extracellular (...) matrix, supporting the hypothesis that regulation through changes in cell tension and architecture play a key role. (shrink)

The vertebrate adaptive immune system has well defined functions in maintaining tolerance to self‐tissues. Suppression of autoreactive T cells is dependent on the regulatory cytokine transforming growth factor‐β (TGF‐β) and regulatory T (Treg) cells, a distinct T cell lineage specified by the transcription factor Foxp3. Although TGF‐β promotes thymic Treg (tTreg) cell development by repressing T cell clonal deletion and peripheral Treg cell differentiation by inducing Foxp3 expression, a recent study shows that TGF‐β suppresses autoreactive T (...) cells independent of Foxp3+ Treg cells. These findings imply that as an ancestral growth factor family member, TGF‐β may have been co‐opted as a T cell‐intrinsic mechanism of self‐tolerance control to assist the evolutionary transition of vertebrate adaptive immunity. Later, perhaps in placental mammals upon their acquisition of a TGF‐β regulatory element in the Foxp3 locus, the TGF‐β pathway is further engaged to induce peripheral Treg cell differentiation and expand the scope of T cell tolerance control to innocuous foreign antigens. (shrink)

The contribution of this present paper is to propose a method that combines a chemical Brusselator reaction-diffusion system with a biological cell system via gap junction for controlling and visualizing the frequency and magnitude of chaotic intracellular calcium oscillations in two cell types, including nonexcitable cells and the glial cells. This produces a wide variety of oscillatory behaviors similar to those reported in numerous biological experiments. We particularly show that in the majority of chaos cases, the reactor to (...) cell coupling can induce the generation of regular calcium oscillations as the coupling strength is varied. Together with the proposed method of coupled models, the regularity of these chaotic oscillations enables us to gain better understanding and extensive insights into the overall coupling dynamics. (shrink)

In circulation, T cells are spherical with selectin enriched dynamic microvilli protruding from the surface. Following extravasation, these microvilli serve another role, continuously surveying their environment for antigen in the form of peptide‐MHC (pMHC) expressed on the surface of antigen presenting cells (APCs). Upon recognition of their cognate pMHC, the microvilli are initially stabilized and then flatten into F‐actin dependent microclusters as the T cell spreads over the APC. Within 1–5 min, clathrin is recruited by the ESCRT‐0 component Hrs (...) to mediate release of T cell receptor (TCR) loaded vesicles directly from the plasma membrane by clathrin and ESCRT‐mediated ectocytosis (CEME). After 5‐10 min, Hrs is displaced by the endocytic clathrin adaptor epsin‐1 to induce clathrin‐mediated trans‐endocytosis (CMTE) of TCR‐pMHC conjugates. Here we discuss some of the functional properties of the clathrin machinery which enables it to control these topologically opposite modes of membrane transfer at the immunological synapse, and how this might be regulated during T cell activation. (shrink)

Receptor tyrosine kinases and integrins are activated by growth factors and extracellular matrix, respectively. Their activation leads to signal transduction cascades that control many aspects of cell phenotype, including progression through the G1 phase of the cell cycle. However, the signalling cassettes driven by growth factors and matrix do not work independently of each other. Integrin triggering is essential to facilitate kinase‐ and GTPase‐mediated signals and thereby drive efficient transfer of information through the growth factor–cyclin axis. A (...) recent study indicates that an additional type of player has a key role in adhesion‐regulated control of cell cycle, namely ubiquitin ligase.(1) BioEssays 24:17–21, 2002. © 2002 John Wiley & Sons, 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)

Spontaneous polarization without spatial cues, or symmetry breaking, is a fundamental problem of spatial organization in biological systems. This question has been extensively studied using yeast models, which revealed the central role of the small GTPase switch Cdc42. Active Cdc42‐GTP forms a coherent patch at the cell cortex, thought to result from amplification of a small initial stochastic inhomogeneity through positive feedback mechanisms, which induces cell polarization. Here, I review and discuss the mechanisms of Cdc42 activity self‐amplification and (...) dynamic turnover. A robust Cdc42 patch is formed through the combined effects of Cdc42 activity promoting its own activation and active Cdc42‐GTP displaying reduced membrane detachment and lateral diffusion compared to inactive Cdc42‐GDP. I argue the role of the actin cytoskeleton in symmetry breaking is not primarily to transport Cdc42 to the active site. Finally, negative feedback and competition mechanisms serve to control the number of polarization sites. (shrink)

Vulval development in the Caenorhabditis elegans hermaphrodite represents a simple, genetically tractable system for studying how cell signaling events control cell fata decisions. Current models suggest that proper specification of vulval cell fates relies on the integration of multiple signaling systems, including one that involves a receptor tyrosine kinase (RTK)→Ras→mitogen activated protein kinase (MAPK) cascade and one that involves a LIN‐12/Notch family receptor. In this review, we first discuss how genetic strategies are being used to identify (...) and analyze components that control vulval cell fate decisions. We then describe the different signaling systems that have been elucidated and how they relate to one another. Finally, we highlight several recently characterized genes that encode positive regulators, negative regulators or potential targets of the RTK→Ras→MAPK cascade involved in vulval induction. (shrink)

The fate of cells arrested in mitosis by antimitotic compounds is complex but is influenced by competition between pathways promoting cell death and pathways promoting mitotic exit. As components of both of these pathways are regulated by Cdc20‐dependent degradation, I hypothesize that variations in Cdc20 protein levels, rather than mutations in checkpoint genes, could affect cell fate during prolonged mitotic arrest. This hypothesis is supported by experiments where manipulation of Cdc20 levels affects the response to antimitotic compounds. The (...) observed differences in Cdc20 levels between cell lines likely reflects differences in the rate of synthesis or degradation of the protein; therefore, understanding these pathways at a molecular level could pave the way for modulating the activity of Cdc20, in turn presenting novel therapeutic possibilities. (shrink)

Wnt signalling through β‐catenin plays a pivotal role during embryonic pattern formation, cell fate determination and tissue homeostasis in the adult organism. In the skin, as in many other tissues, Wnt/β‐catenin signalling can control lineage determination and differentiation. However, it was not known whether Wnt/β‐catenin signalling is an immediate regulator of the stem cell niche in skin tissue. A recent publication now provides evidence that Wnt/β‐catenin signalling exerts a direct effect on the stem cell compartment by (...) inducing quiescent stem cells to enter the cell cycle during early stages of hair follicle regeneration. In addition, the authors demonstrate that β‐catenin is required for maintenance of the stem cell pool in the tissue.1 The data suggest that a gradient in Wnt/β‐catenin activity levels can induce different responses within distinct cell populations reflected by activation of distinct transcriptional profiles. BioEssays 28:1–5, 2006. © 2005 Wiley Periodicals, Inc. (shrink)

Plant reproduction is vital for species survival, and is also central to the production of food for human consumption. Seeds result from the successful fertilization of male and female gametes, but our understanding of the development, differentiation of gamete lineages and fertilization processes in higher plants is limited. Germ cells in animals diverge from somatic cells early in embryo development, whereas plants have distinct vegetative and reproductive phases in which gametes are formed from somatic cells after the plant has made (...) the transition to flowering and the formation of the reproductive organs. Recently, novel insights into the molecular mechanisms underlying male germ‐line initiation and male gamete development in plants have been obtained. Transcriptional repression of male germ‐line genes in non‐male germ‐line cells have been identified as a key mechanism for spatial and temporal control of male germ‐line development. This review focuses on molecular events controlling male germ‐line development especially, on the nature and regulation of gene expression programs operating in male gametes of flowering plants. BioEssays 29:1124–1132, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Valuable insights into eukaryotic regulatory circuits can emerge from studying interactions of bacterial pathogens such as Helicobacter pylori with host tissues. H. pylori uses a type IV secretion system (T4SS) to deliver its CagA virulence protein to epithelial cells, where much of it becomes phosphorylated. CagA's phosphorylated and non‐phosphorylated forms each interact with host regulatory proteins to alter cell structure and cell fate. Kwok and colleagues1 showed that CagA destined for phosphorylation is delivered using host integrin as receptor (...) and H. pylori's CagL protein as an integrin‐specific adhesin, and that CagL–integrin‐binding activates the kinase cascade responsible for CagA phosphorylation. This research contributes to understanding infectious disease and the control of cell fates. BioEssays 30:515–520, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Cell communication is crucial for many aspects of growth and differentiation during the development of the nematode Caenorhabditis elegans. Two genes, glp‐1 and lin‐12, mediate a number of known cell–cell interactions. Genetic and molecular analyses of these two genes lead to the conclusion that they are structurally and functionally related. We summarize these studies as well as those involving the identification of other genes that interact with glp‐1 and / or lin‐12.