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Cell-cell signaling and adhesion in phagocytosis and early development of Dictyostelium.

Cell-cell signaling and adhesion regulate transition from the unicellular to the multicellular stage of development in the cellular slime mold Dictyostelium. Essential gene networks involved in these processes have been identified and their interplay dissected. Heterotrimeric G protein-linked signal transduction plays a key role in regulating expression of genes mediating chemotaxis or cell adhesion, as well as coordinating actin-based cell motility during phagocytosis and chemotaxis. Two classes of cell adhesion molecules, one cadherin-like and the second belonging to the IgG superfamily, contribute to the strength of adhesion in Dictyostelium aggregates. The developmental role of genes involved in motility and adhesion, and their degree of redundancy, have been re-assessed by using novel developmental assay conditions which are closer to development in nature.

Animals↗

Defining the networks that connect RNase III and RNase J-mediated regulation of primary and specialized metabolism in Streptomyces venezuelae.

UNLABELLED: RNA metabolism involves coordinating RNA synthesis with RNA processing and degradation. Ribonucleases play fundamental roles within the cell, contributing to the cleavage, modification, and degradation of RNA molecules, with these actions ensuring appropriate gene regulation and cellular homeostasis. Here, we employed RNA sequencing to explore the impact of RNase III and RNase J on the transcriptome of Streptomyces venezuelae. Differential expression analysis comparing wild-type and RNase mutant strains at distinct developmental stages revealed significant changes in transcript abundance, particularly in pathways related to multicellular development, nutrient acquisition, and specialized metabolism. Both RNase mutants exhibited dysregulation of the BldD regulon, including altered expression of many cyclic-di-GMP-associated enzymes. We also observed precocious chloramphenicol production in these RNase mutants and found that in the RNase III mutant, this was associated with PhoP-mediated regulation. We further found that RNase III directly targeted members of the PhoP regulon, suggesting a link between RNA metabolism and a regulator that bridges primary and specialized metabolism. We connected RNase J function with translation through the observation that RNase J directly targets multiple ribosomal protein transcripts for degradation. These findings establish distinct but complementary roles for RNase III and RNase J in coordinating the gene expression dynamics critical for S. venezuelae development and specialized metabolism. IMPORTANCE: RNA processing and metabolism are mediated by ribonucleases and are fundamental processes in all cells. In the morphologically complex and metabolically sophisticated Streptomyces bacteria, RNase III and RNase J influence both development and metabolism through poorly understood mechanisms. Here, we show that both ribonucleases are required for the proper expression of the BldD developmental pathway and contribute to the control of chloramphenicol production, with an interesting connection to phosphate regulation for RNase III. Additionally, we show that both RNases have the potential to impact translation through distinct mechanisms and can function cooperatively in degrading specific transcripts. This study advances our understanding of RNases in Streptomyces biology by providing insight into distinct contributions made by these enzymes and the intriguing interplay between them.

Streptomyces↗

The tenascin family of ECM glycoproteins: structure, function, and regulation during embryonic development and tissue remodeling.

The determination of animal form depends on the coordination of events that lead to the morphological patterning of cells. This epigenetic view of development suggests that embryonic structures arise as a consequence of environmental influences acting on the properties of cells, rather than an unfolding of a completely genetically specified and preexisting invisible pattern. Specialized cells of developing multicellular organisms are surrounded by a complex extracellular matrix (ECM), comprised largely of different collagens, proteoglycans, and glycoproteins. This ECM is a substrate for tissue morphogenesis, lends support and flexibility to mature tissues, and acts as an epigenetic informational entity in the sense that it transduces and integrates intracellular signals via distinct cell surface receptors. Consequently, ECM-receptor interactions have a profound influence on major cellular programs including growth, differentiation, migration, and survival. In contrast to many other ECM proteins, the tenascin (TN) family of glycoproteins (TN-C, TN-R, TN-W, TN-X, and TN-Y) display highly restricted and dynamic patterns of expression in the embryo, particularly during neural development, skeletogenesis, and vasculogenesis. These molecules are reexpressed in the adult during normal processes such as wound healing, nerve regeneration, and tissue involution, and in pathological states including vascular disease, tumorigenesis, and metastasis. In concert with a multitude of associated ECM proteins and cell surface receptors that include members of the integrin family, TN proteins impart contrary cellular functions, depending on their mode of presentation (i.e., soluble or substrate-bound) and the cell types and differentiation states of the target tissues. Expression of tenascins is regulated by a variety of growth factors, cytokines, vasoactive peptides, ECM proteins, and biomechanical factors. The signals generated by these factors converge on particular combinations of cis-regulatory elements within the recently identified TN gene promoters via specific transcriptional activators or repressors. Additional complexity in regulating TN gene expression is achieved through alternative splicing, resulting in variants of TN polypeptides that exhibit different combinations of functional protein domains. In this review, we discuss some of the recent advances in TN biology that provide insights into the complex way in which the ECM is regulated and how it functions to regulate tissue morphogenesis and gene expression.

Adult↗

Mechanism and control of meiotic recombination initiation.

Homologous recombination is essential during meiosis in most sexually reproducing organisms. In budding yeast, and most likely in other organisms as well, meiotic recombination proceeds via the formation and repair of DNA double-strand breaks (DSBs). These breaks appear to be formed by the Spo11 protein, with assistance from a large number of other gene products, by a topoisomerase-like transesterase mechanism. Recent studies in fission yeast, multicellular fungi, flies, worms, plants, and mammals indicate that the role of Spo11 in meiotic recombination initiation is highly conserved. This chapter reviews the properties of Spo11 and the other gene products required for meiotic DSB formation in a number of organisms and discusses ways in which recombination initiation is coordinated with other events occurring in the meiotic cell.

Amino Acid Sequence↗

Left-right asymmetry: nodal points.

The striking left-right asymmetry of visceral organs is known to depend on left- and right-side-specific cascades of gene expression during early embryogenesis. Now, developmental biologists are characterizing the earliest steps in asymmetry determination that dictate the sidedness of asymmetric gene expression. The proteins and structures involved control fascinating physiological processes, such as extracellular fluid flow and membrane voltage potential and yet little is known about how their activities are coordinated to control laterality. By analogy with intercellular signalling in certain epithelial and endothelial cells, however, it is reasonable to speculate that at least three of these players, monocilia, gap junction communication and the Ca2+ channel polycystin-2, participate in a signalling pathway that propagates left-right cues through multicellular fields.

Animals↗

A three-dimensional vertex dynamics cell model of space-filling polyhedra simulating cell behavior in a cell aggregate.

We developed a three-dimensional (3D) cell model of a multicellular aggregate consisting of several polyhedral cells to investigate the deformation and rearrangement of cells under the influence of external forces. The polyhedral cells fill the space in the aggregate without gaps or overlaps, consist of contracting interfaces and maintain their volumes. The interfaces and volumes were expressed by 3D vertex coordinates. Vertex movements obey equations of motion that rearrange the cells to minimize total free energy, and undergo an elementary process that exchanges vertex pair connections when vertices approach each other. The total free energy includes the interface energy of cells and the compression or expansion energy of cells. Computer simulations provided the following results: An aggregate of cells becomes spherical to minimize individual cell surface areas; Polygonal interfaces of cells remain flat; Cells within the 3D cell aggregate can move and rearrange despite the absence of free space. We examined cell rearrangement to elucidate the viscoelastic properties of the aggregate, e.g. when an external force flattens a cell aggregate (e.g. under centrifugation) its component cells quickly flatten. Under a continuous external force, the cells slowly rearrange to recover their original shape although the cell aggregate remains flat. The deformation and rearrangement of individual cells is a two-step process with a time lag. Our results showed that morphological and viscoelastic properties of the cell aggregate with long relaxation time are based on component cells where minimization of interfacial energy of cells provides a motive force for cell movement.

Animals↗

Phenotypic differentiation and seeding dispersal in non-mucoid and mucoid Pseudomonas aeruginosa biofilms.

There is growing evidence that Pseudomonas aeruginosa biofilms exhibit a multicellular developmental life cycle analogous to that of the myxobacteria. In non-mucoid PAO1 biofilms cultured in glass flow cells the phenotypic differentiation of microcolonies into a motile phenotype in the interior of the microcolony and a non-motile surrounding 'wall phenotype' are described. After differentiation the interior cells coordinately evacuated the microcolony from local break out points and spread over the wall of the flow cell, suggesting that the specialized microcolonies were analogous to crude fruiting bodies. A microcolony diameter of approximately 80 microm was required for differentiation, suggesting that regulation was related to cell density and mass transfer conditions. This phenomenon was termed 'seeding dispersal' to differentiate it from 'erosion' which is the passive removal of single cells by fluid shear. Using the flow cell culturing method, in which reproducible seeding phenotype in PAO1 wild-type was demonstrated, the effects of quorum sensing (QS) and rhamnolipid production (factors previously identified as important in determining biofilm structure) on seeding dispersal using knockout mutants isogenic with PAO1 was investigated. Rhamnolipid (rhlA) was not required for seeding dispersal but las/rhl QS (PAO1-JP2) was, in our system. To assess the clinical relevance of these data, mucoid P. aeruginosa cystic fibrosis isolate FRD1 was also investigated and was seeding-dispersal-negative.

Biofilms↗

Calcineurin-binding protein Cbp1 directs the specificity of calcineurin-dependent hyphal elongation during mating in Cryptococcus neoformans.

Mating and virulence of the human fungal pathogen Cryptococcus neoformans are controlled by calcineurin, a serine-threonine-specific calcium-activated phosphatase that is the target of the immunosuppressive drugs cyclosporine A and FK506. In previous studies, a calcineurin binding protein (Cbp1, Rcn1, Dscr1/Csp1-3/MCIP1-3) that is conserved from yeasts to humans has been identified, but whether this protein functions to regulate calcineurin activity or facilitate calcineurin function as a signaling effector has been unclear. Here we show that, like calcineurin, Cbp1 is required for mating in C. neoformans. By contrast, Cbp1 plays no role in promoting calcineurin-dependent growth at 37 degrees C and is not essential for haploid fruiting. Site-directed mutagenesis studies provide evidence that tandem phosphorylation and dephosphorylation of two serine residues in the conserved SP repeat motif are critical for Cbp1 function. Epistasis analysis supports models in which Cbp1 functions coordinately with calcineurin to direct hyphal elongation during mating. Taken together, these findings provide insights into the roles of Cbp1 as an accessory subunit or effector of calcineurin-specific signaling pathways, which may be features conserved among the calcipressins to govern calcineurin signaling in immune cells, cardiomyocytes, and neurons of multicellular eukaryotes.

Calcineurin↗

Ca2+ signaling and early embryonic patterning during the blastula and gastrula periods of zebrafish and Xenopus development.

It has been proposed that Ca(2+) signaling, in the form of pulses, waves and steady gradients, may play a crucial role in key pattern forming events during early vertebrate development [L.F. Jaffe, Organization of early development by calcium patterns, BioEssays 21 (1999) 657-667; M.J. Berridge, P. Lipp, M.D. Bootman, The versatility and universality of calcium signaling, Nat. Rev. Mol. Cell Biol. 1 (2000) 11-21; S.E. Webb, A.L. Miller, Calcium signalling during embryonic development, Nat. Rev. Mol. Cell Biol. 4 (2003) 539-551]. With reference to the embryos of zebrafish (Danio rerio) and the frog, Xenopus laevis, we review the Ca(2+) signals reported during the Blastula and Gastrula Periods. This developmental window encompasses the major pattern forming events of epiboly, involution, and convergent extension, which result in the establishment of the basic germ layers and body axes [C.B. Kimmel, W.W. Ballard, S.R. Kimmel, B. Ullmann, T.F. Schilling, Stages of embryonic development of the zebrafish, Dev. Dyn. 203 (1995) 253-310]. Data will be presented to support the suggestion that propagating waves (both long and short range) of Ca(2+) release, followed by sequestration, may play a crucial role in: (1) Coordinating cell movements during these pattern forming events and (2) Contributing to the establishment of the basic embryonic axes, as well as (3) Helping to define the morphological boundaries of specific tissue domains and embryonic structures, including future organ anlagen [E. Gilland, A.L. Miller, E. Karplus, R. Baker, S.E. Webb, Imaging of multicellular large-scale rhythmic calcium waves during zebrafish gastrulation, Proc. Natl. Acad. Sci. USA 96 (1999) 157-161; J.B. Wallingford, A.J. Ewald, R.M. Harland, S.E. Fraser, Calcium signaling during convergent extension in Xenopus, Curr. Biol. 11 (2001) 652-661]. The various potential targets of these Ca(2+) transients will also be discussed, as well as how they might integrate with other known pattern forming pathways known to modulate early developmental events (such as the Wnt/Ca(2+)pathway; [T.A. Westfall, B. Hjertos, D.C. Slusarski, Requirement for intracellular calcium modulation in zebrafish dorsal-ventral patterning, Dev. Biol. 259 (2003) 380-391]).

Animals↗

Mechanism of receptor-oriented intercellular calcium wave propagation in hepatocytes.

Intercellular calcium signals are propagated in multicellular hepatocyte systems as well as in the intact liver. The stimulation of connected hepatocytes by glycogenolytic agonists induces reproducible sequences of intracellular calcium concentration increases, resulting in unidirectional intercellular calcium waves. Hepatocytes are characterized by a gradient of vasopressin binding sites from the periportal to perivenous areas of the cell plate in hepatic lobules. Also, coordination of calcium signals between neighboring cells requires the presence of the agonist at each cell surface as well as gap junction permeability. We present a model based on the junctional coupling of several hepatocytes differing in sensitivity to the agonist and thus in the intrinsic period of calcium oscillations. In this model, each hepatocyte displays repetitive calcium spikes with a slight phase shift with respect to neighboring cells, giving rise to a phase wave. The orientation of the apparent calcium wave is imposed by the direction of the gradient of hormonal sensitivity. Calcium spikes are coordinated by the diffusion across junctions of small amounts of inositol 1,4, 5-trisphosphate (InsP(3)). Theoretical predictions from this model are confirmed experimentally. Thus, major physiological insights may be gained from this model for coordination and spatial orientation of intercellular signals.-Dupont, G., Tordjmann, T., Clair, C., Swillens, S., Claret, M., Combettes, L. Mechanism of receptor-oriented intercellular calcium wave propagation in hepatocytes.

Animals↗

Three abundant germ line-specific transcripts in Volvox carteri encode photosynthetic proteins.

Volvox carteri is a multicellular eukaryotic green alga composed of about 2000 cells of only two differentiated types: somatic and germ line. To understand how embryonic cells are assigned either to somatic or germ line fates, we are investigating the regulation of transcripts that are abundant in only one cell type. Here we report the identity of three transcripts that are coordinately expressed at high levels in germ line cells but not in somatic cells. Surprisingly, all three transcripts encode photosynthetic chloroplast proteins (light-harvesting complex protein, oxygen-evolving enhancer protein 3, and ferredoxin-NADP+ reductase) that are transcribed from nuclear genes. We discuss why these mRNAs might be required at high levels in germ line cells and present a hypothesis, suggested by our results, on the evolution of cell specialization in the Volvocales.

Algal Proteins↗

Common origin and phylogenetic diversification of animal hormonal systems.

The comparative view leads to the following main conclusions: Hormones are intercellular messengers in multicellular organisms. However, the receptor mechanism, the ability of forming receptors to substances in the cell's environment and the ability to synthesize most of the substances which serve as hormones in metazoans, are present in unicellular organisms, too. The main achievement of multicellular organisms in evolving hormonal mechanisms is due to their ability of differentiation. Though the whole genome and the ability to synthesize certain substances is, in principle, common to all body cells, the forming of certain substances and the ability to react to them in a certain way is delegated to certain cell groups only. This may be common to many intercellular messenger substances such as chalons, prostaglandins, morphogenetic and tissue-specific growth substances. A special feature in hormonal systems is that the two sites of release and reaction are distinct and are located at a distance from each other. Possibly this is the main or even the only difference from other intercellular messengers. However, it is of great functional importance because it enables hormones to control the temporal coordination of entirely different processes in different tissues located at a distance from each other or distributed all over the body. This feature is common to all compounds presently known as hormones. While the localization of receptors in target cells, as well as the nature of the releasing tissue or the mode of transport through the blood, may be too marrow borders for a definition (for instance in animal groups without a closed blood circulation system) the fact that there is transport over a distance is not. The fact that release and reaction sites are located at a distance from each other within the multicellular body may serve as a definition of "hormones' based on a common phylogenetic root and functional importance. On this common base different animal phyla have evolved different hormonal systems in relation to the particular problems of long distance temporal control of physiological processes posed by their special type of organization.

Animals↗

Individual versus social complexity, with particular reference to ant colonies.

Insect societies colonies of ants, bees, wasps and termites--vary enormously in their social complexity. Social complexity is a broadly used term that encompasses many individual and colony-level traits and characteristics such as colony size, polymorphism and foraging strategy. A number of earlier studies have considered the relationships among various correlates of social complexity in insect societies; in this review, we build upon those studies by proposing additional correlates and show how all correlates can be integrated in a common explanatory framework. The various correlates are divided among four broad categories (sections). Under 'polyphenism' we consider the differences among individuals, in particular focusing upon 'caste' and specialization of individuals. This is followed by a section on 'totipotency' in which we consider the autonomy and subjugation of individuals. Under this heading we consider various aspects such as intracolony conflict, worker reproductive potential and physiological or morphological restrictions which limit individuals' capacities to perform a range of tasks or functions. A section entitled 'organization of work' considers a variety of aspects, e.g. the ability to tackle group, team or partitioned tasks, foraging strategies and colony reliability and efficiency. A final section, 'communication and functional integration', considers how individual activity is coordinated to produce an integrated and adaptive colony. Within each section we use illustrative examples drawn from the social insect literature (mostly from ants, for which there is the best data) to illustrate concepts or trends and make a number of predictions concerning how a particular trait is expected to correlate with other aspects of social complexity. Within each section we also expand the scope of the arguments to consider these relationships in a much broader sense of'sociality' by drawing parallels with other 'social' entities such as multicellular individuals, which can be understood as 'societies' of cells. The aim is to draw out any parallels and common causal relationships among the correlates. Two themes run through the study. The first is the role of colony size as an important factor affecting social complexity. The second is the complexity of individual workers in relation to the complexity of the colony. Consequently, this is an ideal opportunity to test a previously proposed hypothesis that 'individuals of highly social ant species are less complex than individuals from simple ant species' in light of numerous social correlates. Our findings support this hypothesis. In summary, we conclude that, in general, complex societies are characterized by large colony size, worker polymorphism, strong behavioural specialization and loss of totipotency in its workers, low individual complexity, decentralized colony control and high system redundancy, low individual competence, a high degree of worker cooperation wher tackling tasks, group foraging strategies, high tempo, multi-chambered tailor-made nests, high functional integration, relatively greater use of cues and modulatory signals to coordinate individuals and heterogeneous patterns of worker-worker interaction.

Animals↗

The key to development: interpreting the histone code?

Developmental stages in multicellular organisms proceed according to a temporally and spatially precise pattern of gene expression. It has become evident that changes within the chromatin structure brought about by covalent modifications of histones are of crucial importance in determining many biological processes, including development. Numerous studies have provided evidence that the enzymes responsible for the modifications of histones function in a coordinated pattern to control gene expression in the short term and, through the transferral of these modifications by inheritance to their progeny, in the long term.

Animals↗

Emerging out of nature into history: the plurality of the sciences.

The idea of a 'theory of everything' is inconsistent with a natural feature of biological evolution: the spontaneous emergence of composite entities with completely new properties. At successively higher levels of complexity, from elementary particles and chemical molecules, through unicellular and multicellular organisms, to self-aware human beings and their cultural institutions, we find systems obeying entirely novel principles. The behaviour of such systems is not predictable from the properties of their constituents, so distinct 'languages' are required to describe them scientifically. The plurality of our sciences is thus an irreducible feature of the universe we live in. In particular, the reversible time coordinate of mathematical physics cannot cope with the natural 'path dependence' of biology. In the human sciences this extends into the imagined future as well as the remembered past. Furthermore, science nowadays usually arises in localized social contexts, where the 'logic of the situation' is continually being transformed by the emergence of cultural novelties such as unpredictable technological innovations. Thus, scientific knowledge cannot be restricted to generalized synchronic models, but involves historical narratives of specific events and unforeseen circumstances.

Adaptation, Physiological↗

A computational model of ameboid deformation and locomotion.

Traditional continuum models of ameboid deformation and locomotion are limited by the computational difficulties intrinsic in free boundary conditions. A new model using the immersed boundary method overcomes these difficulties by representing the cell as a force field immersed in fluid domain. The forces can be derived from a direct mechanical interpretation of such cell components as the cell membrane, the actin cortex, and the transmembrane adhesions between the cytoskeleton and the substratum. The numerical cytoskeleton, modeled as a dynamic network of immersed springs, is able to qualitatively model the passive mechanical behavior of a shear-thinning viscoelastic fluid (Bottino 1997). The same network is used to generate active protrusive and contractile forces. When coordinated with the attachment-detachment cycle of the cell's adhesions to the substratum, these forces produce directed locomotion of the model ameba. With this model it is possible to study the effects of altering the numerical parameters upon the motility of the model cell in a manner suggestive of genetic deletion experiments. In the context of this ameboid cell model and its numerical implementation, simulations involving multicellular interaction, detailed internal signaling, and complex substrate geometries are tractable.

Actins↗

Cellular reaction to hypoxia: sensing and responding to an adverse environment.

Multicellular organisms have developed sophisticated physiologic mechanisms by which they maintain their tissues at the optimal oxygen concentration. This level is important so that the benefits of free oxygen can be realized, while limiting the potential harms. Despite these efforts, there exist physiologic and pathophysiologic conditions where oxygen delivery drops below what is necessary for the tissue. Under these circumstances, the cell then goes through a series of coordinated responses in a time and oxygen concentration-dependent manner. The gene expression changes are designed to maintain cellular and tissue viability, and are comprised of transcriptional as well as post-transcriptional events. As we understand more about the hypoxic response, we realize how it can impact normal development, wound healing, and the malignant progression of a solid tumor.

Adaptation, Physiological↗

Observations on the migratory behaviour of Schwann cells from adult peripheral nerve explant cultures.

The migration of Schwann cells from adult sciatic nerve explant cultures has been examined by time-lapse photomicrography. Analysis of Schwann cell migratory behaviour indicates that the initial outwandering by individual Schwann cells was random. Although chance cell-cell contacts resulted in temporary immobilization of pairs of cells, stable multicellular structures did not form during this initial phase. As local cell densities increased, Schwann cells assembled networks within which Schwann cell movement continued to be observed. A second form of Schwann cell outgrowth was observed from degenerating fibres in which arrays of highly oriented Schwann cells migrated away from their basal lamina tubes onto the culture dish. These observations of Schwann cell random migration, network self-assembly and coordinated extratubal migration are considered to highlight aspects of Schwann cell behaviour, independent of axonal influences, which may have relevance to their role in peripheral nerve repair following nerve section.

Animals↗