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At least 19 recordsLinked to original sources

How amoeboids self-organize into a fruiting body: multicellular coordination in Dictyostelium discoideum.

When individual amoebae of the cellular slime mold Dictyostelium discoideum are starving, they aggregate to form a multicellular migrating slug, which moves toward a region suitable for culmination. The culmination of the morphogenesis involves complex cell movements that transform a mound of cells into a globule of spores on a slender stalk. The movement has been likened to a "reverse fountain," whereby prestalk cells in the upper part form a stalk that moves downwards and anchors to the substratum, while prespore cells in the lower part move upwards to form the spore head. So far, however, no satisfactory explanation has been produced for this process. Using a computer simulation that we developed, we now demonstrate that the processes that are essential during the earlier stages of the morphogenesis are in fact sufficient to produce the dynamics of the culmination stage. These processes are cAMP signaling, differential adhesion, cell differentiation, and production of extracellular matrix. Our model clarifies the processes that generate the observed cell movements. More specifically, we show that periodic upward movements, caused by chemotactic motion, are essential for successful culmination, because the pressure waves they induce squeeze the stalk downwards through the cell mass. The mechanisms revealed by our model have a number of self-organizing and self-correcting properties and can account for many previously unconnected and unexplained experimental observations.

Animals↗

Thinking about bacterial populations as multicellular organisms.

It has been a decade since multicellularity was proposed as a general bacterial trait. Intercellular communication and multicellular coordination are now known to be widespread among prokaryotes and to affect multiple phenotypes. Many different classes of signaling molecules have been identified in both Gram-positive and Gram-negative species. Bacteria have sophisticated signal transduction networks for integrating intercellular signals with other information to make decisions about gene expression and cellular differentiation. Coordinated multicellular behavior can be observed in a variety of situations, including development of E. coli and B. subtilis colonies, swarming by Proteus and Serratia, and spatially organized interspecific metabolic cooperation in anaerobic bioreactor granules. Bacteria benefit from multicellular cooperation by using cellular division of labor, accessing resources that cannot effectively be utilized by single cells, collectively defending against antagonists, and optimizing population survival by differentiating into distinct cell types.

Bacillus subtilis↗

The NmpRSTU multi-component signaling system of Myxococcus xanthus regulates expression of an oxygen utilization regulon.

UNLABELLED: Myxococcus xanthus has numerous two-component signaling systems (TCSs), many of which regulate the complex social behaviors of this soil bacterium. A subset of TCSs consists of NtrC-like response regulators (RRs) and their cognate histidine sensor kinases (SKs). We have previously demonstrated that a multi-component, phosphorelay TCS named NmpRSTU plays a role in M. xanthus social motility. NmpRSTU was discovered through a screen that identified mutations in nmp genes that restored Type-IV pili-dependent motility to a nonmotile strain. The Nmp pathway begins with the SK NmpU, which is predicted to be active in the presence of oxygen. NmpU phosphorylates another SK, NmpS, a hybrid kinase containing an RR domain and a HisKA-CA domain. These two kinases work in a reciprocal fashion: when NmpU is active, NmpS is inactive, and vice versa. Finally, the phosphorelay culminates in NmpS phosphorylating the NtrC-like RR NmpR. To better understand the role of NmpRSTU in M. xanthus physiology, we determined the NmpR regulon by combining in silico predictions of the NmpR consensus binding sequence with in vitro electromobility shift assays (EMSAs) and in vivo transcriptional reporters. We identified several NmpR-dependent, upregulated genes likely to be important in oxygen utilization. Additionally, we demonstrate NmpRSTU plays a role in fruiting body development, suggesting a role for oxygen sensing in this behavior. We propose that NmpRSTU senses oxygen-limiting conditions, and NmpR upregulates genes associated with optimal utilization of that oxygen. This may be necessary for M. xanthus physiology and behaviors in the highly dynamic soil where oxygen concentrations vary dramatically. IMPORTANCE: Bacteria use two-component signaling systems (TCSs) to respond to a multitude of environmental signals and subsequently regulate complex cellular physiology and behaviors. Myxococcus xanthus is a ubiquitous soil bacterium that encodes numerous two-component systems to respond to the conditions of its soil environment and coordinate multicellular behaviors such as coordinated motility, microbial predation, fruiting body development, and sporulation. To better understand how this bacterium uses a two-component system that has been linked to the sensing of oxygen concentrations, NmpRSTU, we determined the gene regulatory network of this system. We identified several genes regulated by NmpR that are likely important in oxygen utilization and for the M. xanthus response to varied oxygen concentrations in the dynamic soil environment.

Myxococcus xanthus↗

The significances of bacterial colony patterns.

Bacteria do many things as organized populations. We have recently learned much about the molecular basis of intercellular communication among prokaryotes. Colonies display bacterial capacities for multicellular coordination which can be useful in nature where bacteria predominantly grow as films, chains, mats and colonies. E. coli colonies are organized into differentiated non-clonal populations and undergo complex morphogenesis. Multicellularity regulates many aspects of bacterial physiology, including DNA rearrangement systems. In some bacterial species, colony development involves swarming (active migration of cell groups). Swarm colony development displays precise geometrical controls and periodic phenomena. Motile E. coli cells in semi-solid media form organized patterns due to chemotactic autoaggregation. On poor media, B. subtilis forms branched colonies using group motility and long-range chemical signalling. The significances of bacterial colony patterns thus reside in a deeper understanding of prokaryotic biology and evolution and in experimental systems for studying self-organization and morphogenesis.

Bacteria↗

Coordination of mesangial cell contraction by gap junction--mediated intercellular Ca(2+) wave.

Gap junction intercellular communication (GJIC) plays a fundamental role in mediating intercellular signals and coordinating multicellular behavior in various tissues and organs. Glomerular mesangial cells (MC) are rich in GJ, but the functional associations of these intercellular channels are still unclear. This study examines the potential role of GJ in the transmission of intercellular Ca(2+) signals and in the coordination of MC contraction. First, the presence of GJ protein Cx43 and functional GJIC was confirmed in MC by using immunochemical staining or transfer of Lucifer yellow (LY) after a single cell injection, respectively. Second, mechanical stimulation of a single MC initiated propagation of an intercellular Ca(2+) wave, which was preventable by the GJ inhibitor heptanol but was not altered by pretreatment of MC with ATP or addition of apyrase into the assay system. Third, the phospholipase C (PLC) inhibitor U73122 could largely eliminate the mechanically elicited propagation of intercellular Ca(2+) waves, suggesting a possibly mediating role of inositol trisphosphate (IP(3)) in the initiation and transmission of intercellular Ca(2+) signaling. Fourth, injection of IP(3) into a single cell caused contraction, not only in the targeted cell, but also in the adjacent cells, as indicated by the reduction of cellular planar area. Fifth, addition of two structurally unrelated GJ inhibitors, heptanol and alpha-glycyrrhetinic acid (GA), into MC embedded in collagen gels significantly attenuated the reduction of gel areas after exposure to serum. This study provides the first functional evidence supporting the critical role of GJIC in the synchronization of MC behaviors.

Animals↗

Integrative radiation carcinogenesis: interactions between cell and tissue responses to DNA damage.

Tissue function requires coordinated multicellular behavior as a consequence of diverse signals integrated through the tissue microenvironment; importantly, these cell-cell and cell-microenvironment interactions also actively suppress cancer. Ionizing radiation (IR) elicits a well-defined cellular response to DNA damage that mediates the fate of the individual cell, concomitantly with a less well-characterized overarching tissue stress response that coordinates the response of multiple cell types via microenvironment signaling. We have now shown that these programs to reestablish homeostasis intersect via mutual regulation by transforming growth factor beta1 (TGF beta 1), which acts as an extracellular sensor and signal of stress. In this review, the concept that this type of functional integration of cell and tissue stress response programs is essential to cancer suppression will be discussed. Our experiments using IR, and several recent studies that experimentally manipulate stromal TGF beta, show that disruption of microenvironment signaling actively promotes malignant progression. Understanding the dynamic interactions between tissue and cell stress responses will be necessary for an accurate assessment of cancer risk and may also provide targets for prevention.

Animals↗

Geometric mechanogenomics: engineering boundary conditions for deterministic cell fate control.

In tissue development and regeneration, cellular behavior has traditionally been interpreted through biochemical signaling frameworks. However, cells exist within physically defined environments, where geometric boundary conditions - including confinement, curvature, anisotropy, and multicellular architecture - define the mechanical state space in which mechanical forces are generated, transmitted, and interpreted. Here, we introduce geometric mechanogenomics, a conceptual framework that positions geometry as an upstream spatial regulator linking tissue-scale boundary conditions to nuclear mechanics, chromatin organization, and genome regulation. We propose a boundary-to-nucleus axis through which geometric information is decoded by adhesion-mediated mechanotransduction, cytoskeletal force transmission, and nuclear mechanoregulation to regulate chromatin accessibility, epigenetic remodeling, and transcriptional programs. Rather than introducing new mechanotransduction pathways, this framework emphasizes that geometry spatially organizes conserved mechanotransductive machinery to generate context-dependent mechanogenomic outcomes. We further discuss how engineered geometries reduce morphogenetic stochasticity, coordinate multicellular organization, and establish mechanical memory that influences long-term cell fate. Finally, we highlight current challenges in establishing predictive geometry-to-genome relationships and discuss emerging opportunities enabled by spatial omics, artificial intelligence-assisted inverse design, and dynamic biomaterials for programmable mechanobiology, regenerative medicine, developmental biology, and disease modeling.

genome organization↗

Extracellular signaling through the microenvironment: a hypothesis relating carcinogenesis, bystander effects, and genomic instability.

Cell growth, differentiation and death are directed in large part by extracellular signaling through the interactions of cells with other cells and with the extracellular matrix; these interactions are in turn modulated by cytokines and growth factors, i.e. the microenvironment. Here we discuss the idea that extracellular signaling integrates multicellular damage responses that are important deterrents to the development of cancer through mechanisms that eliminate abnormal cells and inhibit neoplastic behavior. As an example, we discuss the action of transforming growth factor beta (TGFB1) as an extracellular sensor of damage. We propose that radiation-induced bystander effects and genomic instability are, respectively, positive and negative manifestations of this homeostatic process. Bystander effects exhibited predominantly after a low-dose or a nonhomogeneous radiation exposure are extracellular signaling pathways that modulate cellular repair and death programs. Persistent disruption of extracellular signaling after exposure to relatively high doses of ionizing radiation may lead to the accumulation of aberrant cells that are genomically unstable. Understanding radiation effects in terms of coordinated multicellular responses that affect decisions regarding the fate of a cell may necessitate re-evaluation of radiation dose and risk concepts and provide avenues for intervention.

Bystander Effect↗

Regulation of gap junctional communication in CFTR-expressing pancreatic epithelial cells.

Gap junction channels provide a pathway for coordinating multicellular activity. To evaluate the contribution of cell-to-cell communication in the function of epithelial cells, we studied the strength of gap junctional coupling in pancreatic acinar and duct cells exposed to agents known to elevate the intracellular concentration of Ca(2+) or cAMP. In acinar cells, we observed that maximal concentrations of acetylcholine evoked a biphasic increase in cytosolic Ca(2+) mobilization. The second sustained phase, which depends on Ca(2+) influx into the cell, was associated with the rapid closure of gap junction channels. In duct cells, stimulation of CFTR-dependent Cl(-) currents with cAMP analogs markedly increased gap junctional conductance in pairs of cells. Interestingly, cAMP had no effect on intercellular communication between cells harboring the DeltaF508 mutation of CFTR. An abnormal pattern of gap junctional coupling may contribute to the altered functions of tissues affected in cystic fibrosis.

Acetylcholine↗

The new bacterial cell biology: moving parts and subcellular architecture.

Recent advances have demonstrated that bacterial cells have an exquisitely organized and dynamic subcellular architecture. Like their eukaryotic counterparts, bacteria employ a full complement of cytoskeletal proteins, localize proteins and DNA to specific subcellular addresses at specific times, and use intercellular signaling to coordinate multicellular events. The striking conceptual and molecular similarities between prokaryotic and eukaryotic cell biology thus make bacteria powerful model systems for studying fundamental cellular questions.

Bacteria↗

Communication in bacteria: an ecological and evolutionary perspective.

Individual bacteria can alter their behaviour through chemical interactions between organisms in microbial communities - this is generally referred to as quorum sensing. Frequently, these interactions are interpreted in terms of communication to mediate coordinated, multicellular behaviour. We show that the nature of interactions through quorum-sensing chemicals does not simply involve cooperative signals, but entails other interactions such as cues and chemical manipulations. These signals might have a role in conflicts within and between species. The nature of the chemical interaction is important to take into account when studying why and how bacteria react to the chemical substances that are produced by other bacteria.

Bacteria↗

Cadherins mediate intercellular mechanical signaling in fibroblasts by activation of stretch-sensitive calcium-permeable channels.

Cells in mechanically active environments form extensive, cadherin-mediated intercellular junctions that are important in tissue remodeling and differentiation. Currently, it is unknown whether adherens junctions in connective tissue fibroblasts transmit mechanical signals and coordinate multicellular adaptations to physical forces. We hypothesized that cadherins mediate intercellular mechanotransduction by activating calcium-permeable, stretch-sensitive channels. Human gingival fibroblasts in suspension were plated on established homotypic monolayer cultures. The cells formed intercellular adherens junctions. Controlled mechanical forces were applied to intercellular junctions by electromagnets acting on cells containing internalized magnetite beads. At early but not later stages of intercellular attachment, force application visibly displaced magnetite bead-loaded cells and induced robust Ca(2+) transients (65 +/- 9.4 nm above base line). Similar Ca(2+) transients were induced by force application to anti-N-cadherin antibody-coated magnetite beads. Ca(2+) responses depended on influx of extracellular Ca(2+) through mechanosensitive channels because both Ca(2+) chelation and gadolinium chloride abolished the response and MnCl(2) quenched fura-2 fluorescence after force application. Force application induced accumulation of microinjected rhodamine-actin at intercellular contacts; actin assembly was inhibited by buffering intracellular calcium fluxes. Our results indicate that mechanical forces applied to adherens junctions activate stretch-sensitive calcium-permeable channels and increase actin polymerization. We suggest that N-cadherins in fibroblasts are intercellular mechanotransducers.

Cadherins↗

Glycosylphosphatidylinositol-anchored proteins are required for cell wall synthesis and morphogenesis in Arabidopsis.

Mutations at five loci named PEANUT1-5 (PNT) were identified in a genetic screen for radially swollen embryo mutants. pnt1 cell walls showed decreased crystalline cellulose, increased pectins, and irregular and ectopic deposition of pectins, xyloglucans, and callose. Furthermore, pnt1 pollen is less viable than the wild type, and pnt1 embryos were delayed in morphogenesis and showed defects in shoot and root meristems. The PNT1 gene encodes the Arabidopsis thaliana homolog of mammalian PIG-M, an endoplasmic reticulum-localized mannosyltransferase that is required for synthesis of the glycosylphosphatidylinositol (GPI) anchor. All five pnt mutants showed strongly reduced accumulation of GPI-anchored proteins, suggesting that they all have defects in GPI anchor synthesis. Although the mutants are seedling lethal, pnt1 cells are able to proliferate for a limited time as undifferentiated callus and do not show the massive deposition of ectopic cell wall material seen in pnt1 embryos. The different phenotype of pnt1 cells in embryos and callus suggest a differential requirement for GPI-anchored proteins in cell wall synthesis in these two tissues and points to the importance of GPI anchoring in coordinated multicellular growth.

Amino Acid Sequence↗

Gliding motility in bacteria: insights from studies of Myxococcus xanthus.

Gliding motility is observed in a large variety of phylogenetically unrelated bacteria. Gliding provides a means for microbes to travel in environments with a low water content, such as might be found in biofilms, microbial mats, and soil. Gliding is defined as the movement of a cell on a surface in the direction of the long axis of the cell. Because this definition is operational and not mechanistic, the underlying molecular motor(s) may be quite different in diverse microbes. In fact, studies on the gliding bacterium Myxococcus xanthus suggest that two independent gliding machineries, encoded by two multigene systems, operate in this microorganism. One machinery, which allows individual cells to glide on a surface, independent of whether the cells are moving alone or in groups, requires the function of the genes of the A-motility system. More than 37 A-motility genes are known to be required for this form of movement. Depending on an additional phenotype, these genes are divided into two subclasses, the agl and cgl genes. Videomicroscopic studies on gliding movement, as well as ultrastructural observations of two myxobacteria, suggest that the A-system motor may consist of multiple single motor elements that are arrayed along the entire cell body. Each motor element is proposed to be localized to the periplasmic space and to be anchored to the peptidoglycan layer. The force to glide which may be generated here is coupled to adhesion sites that move freely in the outer membrane. These adhesion sites provide a specific contact with the substratum. Based on single-cell observations, similar models have been proposed to operate in the unrelated gliding bacteria Flavobacterium johnsoniae (formerly Cytophaga johnsonae), Cytophaga strain U67, and Flexibacter polymorphus (a filamentous glider). Although this model has not been verified experimentally, M. xanthus seems to be the ideal organism with which to test it, given the genetic tools available. The second gliding motor in M. xanthus controls cell movement in groups (S-motility system). It is dependent on functional type IV pili and is operative only when cells are in close proximity to each other. Type IV pili are known to be involved in another mode of bacterial surface translocation, called twitching motility. S-motility may well represent a variation of twitching motility in M. xanthus. However, twitching differs from gliding since it involves cell movements that are jerky and abrupt and that lack the organization and smoothness observed in gliding. Components of this motor are encoded by genes of the S-system, which appear to be homologs of genes involved in the biosynthesis, assembly, and function of type IV pili in Pseudomonas aeruginosa and Neisseria gonorrhoeae. How type IV pili generate force in S-motility is currently unknown, but it is to be expected that ongoing physiological, genetic, and biochemical studies in M. xanthus, in conjunction with studies on twitching in P. aeruginosa and N. gonorrhoeae, will provide important insights into this microbial motor. The two motility systems of M. xanthus are affected to different degrees by the MglA protein, which shows similarity to a small GTPase. Bacterial chemotaxis-like sensory transduction systems control gliding motility in M. xanthus. The frz genes appear to regulate gliding movement of individual cells and movement by the S-motility system, suggesting that the two motors found in this bacterium can be regulated to result in coordinated multicellular movements. In contrast, the dif genes affect only S-system-dependent swarming.

Genes, Bacterial↗

Evidence for heteromeric gap junction channels formed from rat connexin43 and human connexin37.

Homomeric gap junction channels are composed solely of one connexin type, whereas heterotypic forms contain two homomeric hemichannels but the six identical connexins of each are different from each other. A heteromeric gap junction channel is one that contains different connexins within either or both hemichannels. The existence of heteromeric forms has been suggested, and many cell types are known to coexpress connexins. To determine if coexpressed connexins would form heteromers, we cotransfected rat connexin43 (rCx43) and human connexin37 (hCx37) into a cell line normally devoid of any connexin expression and used dual whole cell patch clamp to compare the observed gap junction channel activity with that seen in cells transfected only with rCx43 or hCx37. We also cocultured cells transfected with hCx37 or rCx43, in which one population was tagged with a fluorescent marker to monitor heterotypic channel activity. The cotransfected cells possessed channel types unlike the homotypic forms of rCx43 or hCx37 or the heterotypic forms. In addition, the noninstantaneous transjunctional conductance-transjunctional voltage (Gj/Vj) relationship for cotransfected cell pairs showed a large range of variability that was unlike that of the homotypic or heterotypic form. The heterotypic cell pairs displayed asymmetric voltage dependence. The results from the heteromeric cell pairs are inconsistent with summed behavior of two independent homotypic populations or mixed populations of homotypic and heterotypic channels types. The Gj/Vj data imply that the connexin-to-connexin interactions are significantly altered in cotransfected cell pairs relative to the homotypic and heterotypic forms. Heteromeric channels are a population of channels whose characteristics could well impact differently from their homotypic counterparts with regard to multicellular coordinated responses.

Animals↗

Defective regulation of gap junctional coupling in cystic fibrosis pancreatic duct cells.

The cystic fibrosis (CF) gene encodes a cAMP-gated Cl- channel (cystic fibrosis transmembrane conductance regulator [CFTR]) that mediates fluid transport across the luminal surfaces of a variety of epithelial cells. We have previously shown that gap junctional communication and Cl- secretion were concurrently regulated by cAMP in cells expressing CFTR. To determine whether intercellular communication and CFTR-dependent secretion are related, we have compared gap junctional coupling in a human pancreatic cell line harboring the DeltaF508 mutation in CFTR and in the same cell line in which the defect was corrected by transfection with wild-type CFTR. Both cell lines expressed connexin45 (Cx45), as evidenced by RT-PCR, immunocytochemistry, and dual patch-clamp recording. Exposure to agents that elevate intracellular cAMP or specifically activate protein kinase A evoked Cl- currents and markedly increased junctional conductance of CFTR-expressing pairs, but not in the parental cells. The latter effect, which was caused by an increase in single-channel activity but not in unitary conductance of Cx45 channels, was not prevented by exposing CFTR-expressing cells to a Cl- channel blocker. We conclude that expression of functional CFTR restored the cAMP-dependent regulation of junctional conductance in CF cells. Direct intercellular communication coordinates multicellular activity in tissues that are major targets of CF manifestations. Consequently, defective regulation of gap junction channels may contribute to the altered functions of tissues affected in CF.

Cell Communication↗

Calcium signalling in tissue: diversity and domain-specific integration of individual cell response in salivary glands.

Organ function requires coordinated multicellular activities, which may require proper control of cell signalling dynamics at the supracellular level. By using high-speed confocal microscopy, we studied how calcium signalling is organised in the dissociated rat parotid gland. Salivary gland function is accomplished primarily by the compartmentalized epithelial domains, acini and ducts, the former involved in the production of primary saliva and the latter involved in its modification. Upon muscarinic stimulation with carbachol, both domains showed an increase in intracellular free calcium concentration ([Ca(2+)]i) with distinctive spatiotemporal kinetics, as indicated by the fluo-3 fluorescence. Acini responded initially, and the ducts followed with a time lag of more than 0.3 second. Cells comprising an acinus responded synchronously, whereas those in the ducts responded heterogeneously with respect to the latency period, magnitude of response and the requirement of extracellular calcium to raise [Ca(2+)]i. ATP also elicited a non-synchronous [Ca(2+)]i response in the duct domain, under a pattern different from that of carbachol. The synchronous oscillations seen in the acinar domain were made asynchronous by octanol, an agent known to inhibit gap-junction function. Accordingly, a gap junction component, connexin 32, was immunolocalised predominantly between the acinar cells. Moreover, expression of the type 2 inositol (1,4,5)-trisphosphate receptor [Ins(1,4,5)P(3)R] was homogeneous in the acinar domain but heterogeneous in the duct domain. Together, these data suggest that the calcium signalling system in salivary glands is constructed specifically according to the tissue architecture.

Adenosine Triphosphate↗

Differential regulation of gap junctions by proinflammatory mediators in vitro.

The development of inflammation is an important component of host defense against infection. The cellular and molecular processes underlying inflammation are well-studied, and it is known that cells of the blood vessel wall, such as endothelial cells and smooth muscle cells, play pivotal roles. Additionally, a wide variety of proinflammatory mediators have been defined, which coordinate the multicellular processes of inflammation. Knowledge of the potential role of blood vessel gap junctional intercellular communication (GJIC) in coordinating the inflammation process, however, is limited. In this study, we report that bacterial lipopolysaccharide (LPS), as well as the proinflammatory cytokines TNF-alpha and IL-1beta, selectively inhibit human myoendothelial GJIC in vitro without affecting GJIC between the respective homologous cell populations. This finding may represent a physiologically relevant component of the inflammatory response to infection. The work also provides some of the first clear evidence suggesting that a single eukaryotic cell can differentially regulate its GJIC between homologous and heterologous cell types in a simultaneous manner.

Cell Communication↗