Systems biology seeks not only to discover the machinery of life but to understand how such machinery is used for control, i.e., for regulation that achieves or maintains a desired, useful end. This ...sort of goal-directed, engineering-centered approach also has deep historical roots in developmental biology. Not surprisingly, developmental biology is currently enjoying an influx of ideas and methods from systems biology. This Review highlights current efforts to elucidate design principles underlying the engineering objectives of robustness, precision, and scaling as they relate to the developmental control of growth and pattern formation. Examples from vertebrate and invertebrate development are used to illustrate general lessons, including the value of integral feedback in achieving set-point control; the usefulness of self-organizing behavior; the importance of recognizing and appropriately handling noise; and the absence of “free lunch.” By illuminating such principles, systems biology is helping to create a functional framework within which to make sense of the mechanistic complexity of organismal development.
Development, regeneration, and even day-to-day physiology require plant and animal cells to make decisions based on their locations. The principles by which cells may do this are deceptively ...straightforward. But when reliability needs to be high—as often occurs during development—successful strategies tend to be anything but simple. Increasingly, the challenge facing biologists is to relate the diverse diffusible molecules, control circuits, and gene regulatory networks that help cells know where they are to the varied, sometimes stringent, constraints imposed by the need for real-world precision and accuracy.
The theory that the spatial organization of cell fate is orchestrated by gradients of diffusing molecules was a major contribution to 20
th century developmental biology. Although the existence of ...morphogens is no longer in doubt, studies on the formation and function of their gradients have yielded far more puzzles than answers. On close inspection, every morphogen gradient seems to use a rich array of regulatory mechanisms, suggesting that the tasks carried out by such systems are far more extensive than previously thought.
Bacterial community acquisition in the infant gut impacts immune education and disease susceptibility. We compared bacterial strains across and within families in a prospective birth cohort of 44 ...infants and their mothers, sampled longitudinally in the first months of each child’s life. We identified mother-to-child bacterial transmission events and describe the incidence of family-specific antibiotic resistance genes. We observed two inheritance patterns across multiple species, where often the mother’s dominant strain is transmitted to the child, but occasionally her secondary strains colonize the infant gut. In families where the secondary strain of B. uniformis was inherited, a starch utilization gene cluster that was absent in the mother’s dominant strain was identified in the child, suggesting the selective advantage of a mother’s secondary strain in the infant gut. Our findings reveal mother-to-child bacterial transmission events at high resolution and give insights into early colonization of the infant gut.
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•Gut bacterial transmission patterns assessed longitudinally in 44 mother-infant pairs•Metagenomic sequencing reveals transmission patterns beyond dominant strains•Mother’s minor strain sometimes colonizes infant, likely driven by functional selection•Some antibiotic resistance genes co-occur in families, suggesting their inheritance
Using longitudinal metagenomic sequencing from 44 mother/child pairs, Yassour et al. characterized mother-to-child strain transmission patterns. While mothers’ dominant strains were often inherited, nondominant secondary strain transmissions were also observed. Microbial functional analysis reveals that inherited maternal secondary strains may have a selective advantage to colonize infant guts.
The microenvironment that metastatic cells engage and take advantage of to form a niche is a significant contributor to metastatic outgrowth. ... the niche may possibly also contribute to cancer stem ...cell resistance to therapeutic intervention.
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How morphogen gradients form has long been a subject of controversy. The strongest support for the view that morphogens do not simply spread by free diffusion has come from a variety of studies of ...the Decapentaplegic (Dpp) gradient of the Drosophila larval wing disc.
In the present study, we initially show how the failure, in such studies, to consider the coupling of transport to receptor-mediated uptake and degradation has led to estimates of transport rates that are orders of magnitude too low, lending unwarranted support to a variety of hypothetical mechanisms, such as “planar transcytosis” and “restricted extracellular diffusion.” Using several independent dynamic methods, we obtain data that are inconsistent with such models and show directly that Dpp transport occurs by simple, rapid diffusion in the extracellular space. We discuss the implications of these findings for other morphogen systems in which complex transport mechanisms have been proposed.
We believe that these findings resolve a major, longstanding question about morphogen gradient formation and provide a solid framework for interpreting experimental observations of morphogen gradient dynamics.
► We describe how FRAP may fail to provide information about morphogen transport ► We show that most Dpp in the fruit fly wing disc is not undergoing transport ► We visualize and quantify free, extracellular diffusion of a small pool of Dpp ► We explain how transport of such a pool accounts for morphogen gradient formation
Gradients of decapentaplegic (Dpp) pattern Drosophila wing imaginal discs, establishing gene expression boundaries at specific locations. As discs grow, Dpp gradients expand, keeping relative ...boundary positions approximately stationary. Such scaling fails in mutants for Pentagone (pent), a gene repressed by Dpp that encodes a diffusible protein that expands Dpp gradients. Although these properties fit a recent mathematical model of automatic gradient scaling, that model requires an expander that spreads with minimal loss throughout a morphogen field. Here, we show that Pent’s actions are confined to within just a few cell diameters of its site of synthesis and can be phenocopied by manipulating non-diffusible Pent targets strictly within the Pent expression domain. Using genetics and mathematical modeling, we develop an alternative model of scaling driven by feedback downregulation of Dpp receptors and co-receptors. Among the model’s predictions is a size beyond which scaling fails—something we observe directly in wing discs.
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•The Dpp morphogen gradient of the Drosophila wing disc scales with disc size•Feedback downregulation of receptors and co-receptors is required for gradient scaling•A mathematical model shows how moving boundaries, growth, and feedback work together•The secreted expander Pentagone does not spread sufficiently to explain scaling
Zhu et al. investigate how a morphogen gradient expands to fit a growing domain. They argue that initial boundary conditions, tissue growth, and feedback downregulation of receptor and co-receptor expression together create a positional information system that scales automatically, yet transiently.
Haploinsufficiency for Nipbl, a cohesin loading protein, causes Cornelia de Lange Syndrome (CdLS), the most common "cohesinopathy". It has been proposed that the effects of Nipbl-haploinsufficiency ...result from disruption of long-range communication between DNA elements. Here we use zebrafish and mouse models of CdLS to examine how transcriptional changes caused by Nipbl deficiency give rise to limb defects, a common condition in individuals with CdLS. In the zebrafish pectoral fin (forelimb), knockdown of Nipbl expression led to size reductions and patterning defects that were preceded by dysregulated expression of key early limb development genes, including fgfs, shha, hand2 and multiple hox genes. In limb buds of Nipbl-haploinsufficient mice, transcriptome analysis revealed many similar gene expression changes, as well as altered expression of additional classes of genes that play roles in limb development. In both species, the pattern of dysregulation of hox-gene expression depended on genomic location within the Hox clusters. In view of studies suggesting that Nipbl colocalizes with the mediator complex, which facilitates enhancer-promoter communication, we also examined zebrafish deficient for the Med12 Mediator subunit, and found they resembled Nipbl-deficient fish in both morphology and gene expression. Moreover, combined partial reduction of both Nipbl and Med12 had a strongly synergistic effect, consistent with both molecules acting in a common pathway. In addition, three-dimensional fluorescent in situ hybridization revealed that Nipbl and Med12 are required to bring regions containing long-range enhancers into close proximity with the zebrafish hoxda cluster. These data demonstrate a crucial role for Nipbl in limb development, and support the view that its actions on multiple gene pathways result from its influence, together with Mediator, on regulation of long-range chromosomal interactions.
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Coordinated organ behavior is crucial for an effective response to environmental stimuli. By studying regeneration of hair follicles in response to patterned hair plucking, we demonstrate that ...organ-level quorum sensing allows coordinated responses to skin injury. Plucking hair at different densities leads to a regeneration of up to five times more neighboring, unplucked resting hairs, indicating activation of a collective decision-making process. Through data modeling, the range of the quorum signal was estimated to be on the order of 1 mm, greater than expected for a diffusible molecular cue. Molecular and genetic analysis uncovered a two-step mechanism, where release of CCL2 from injured hairs leads to recruitment of TNF-α-secreting macrophages, which accumulate and signal to both plucked and unplucked follicles. By coupling immune response with regeneration, this mechanism allows skin to respond predictively to distress, disregarding mild injury, while meeting stronger injury with full-scale cooperative activation of stem cells.
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•Quorum sensing underlies collective regenerative behavior in a hair follicle population•Sensing occurs via injury → CCL2 → macrophage → TNF-α → hair regeneration pathway•Coupling molecular diffusion and cell mobility achieves a long signaling length scale•Stem cell social behavior can be exploited to enhance the reliability of regeneration
Organ-level quorum sensing through a multi-step immune cascade allows collective regeneration of hair follicle populations. This mechanism provides a means to assess the magnitude and extent of injury that the skin has sustained and make an all-or-none decision whether to regenerate.
It is widely accepted that the growth and regeneration of tissues and organs is tightly controlled. Although experimental studies are beginning to reveal molecular mechanisms underlying such control, ...there is still very little known about the control strategies themselves. Here, we consider how secreted negative feedback factors ("chalones") may be used to control the output of multistage cell lineages, as exemplified by the actions of GDF11 and activin in a self-renewing neural tissue, the mammalian olfactory epithelium (OE). We begin by specifying performance objectives-what, precisely, is being controlled, and to what degree-and go on to calculate how well different types of feedback configurations, feedback sensitivities, and tissue architectures achieve control. Ultimately, we show that many features of the OE-the number of feedback loops, the cellular processes targeted by feedback, even the location of progenitor cells within the tissue-fit with expectations for the best possible control. In so doing, we also show that certain distinctions that are commonly drawn among cells and molecules-such as whether a cell is a stem cell or transit-amplifying cell, or whether a molecule is a growth inhibitor or stimulator-may be the consequences of control, and not a reflection of intrinsic differences in cellular or molecular character.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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