The Experts below are selected from a list of 8913 Experts worldwide ranked by ideXlab platform
Qing Nie - One of the best experts on this subject based on the ideXlab platform.
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Visualizing retinoic acid Morphogen gradients.
Methods in Cell Biology, 2016Co-Authors: Thomas F. Schilling, Julian Sosnik, Qing NieAbstract:Abstract Morphogens were originally defined as secreted signaling molecules that diffuse from local sources to form concentration gradients, which specify multiple cell fates. More recently Morphogen gradients have been shown to incorporate a range of mechanisms including short-range signal activation, transcriptional/translational feedback, and temporal windows of target gene induction. Many critical cell–cell signals implicated in both embryonic development and disease, such as Wnt, fibroblast growth factor (Fgf), hedgehog (Hh), transforming growth factor beta (TGFb), and retinoic acid (RA), are thought to act as Morphogens, but key information on signal propagation and ligand distribution has been lacking for most. The zebrafish provides unique advantages for genetics and imaging to address gradients during early embryonic stages when Morphogens help establish major body axes. This has been particularly informative for RA, where RA response elements (RAREs) driving fluorescent reporters as well as Fluorescence Resonance Energy Transfer (FRET) reporters of receptor binding have provided evidence for gradients, as well as regulatory mechanisms that attenuate noise and enhance gradient robustness in vivo. Here we summarize available tools in zebrafish and discuss their utility for studying dynamic regulation of RA Morphogen gradients, through combined experimental and computational approaches.
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free extracellular diffusion creates the dpp Morphogen gradient of the drosophila wing disc
Current Biology, 2012Co-Authors: Shaohua Zhou, Qing Nie, Jeffrey L Suhalim, Michelle A Digman, Enrico Gratton, Arthur D LanderAbstract:Summary Background 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. Results 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. Conclusions 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.
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noise drives sharpening of gene expression boundaries in the zebrafish hindbrain
Molecular Systems Biology, 2012Co-Authors: Lei Zhang, Thomas F. Schilling, Kelly Radtke, Likun Zheng, Anna Q Cai, Qing NieAbstract:Morphogens provide positional information for spatial patterns of gene expression during development. However, stochastic effects such as local fluctuations in Morphogen concentration and noise in signal transduction make it difficult for cells to respond to their positions accurately enough to generate sharp boundaries between gene expression domains. During development of rhombomeres in the zebrafish hindbrain, the Morphogen retinoic acid (RA) induces expression of hoxb1a in rhombomere 4 (r4) and krox20 in r3 and r5. Fluorescent in situ hybridization reveals rough edges around these gene expression domains, in which cells co-express hoxb1a and krox20 on either side of the boundary, and these sharpen within a few hours. Computational analysis of spatial stochastic models shows, surprisingly, that noise in hoxb1a/krox20 expression actually promotes sharpening of boundaries between adjacent segments. In particular, fluctuations in RA initially induce a rough boundary that requires noise in hoxb1a/krox20 expression to sharpen. This finding suggests a novel noise attenuation mechanism that relies on intracellular noise to induce switching and coordinate cellular decisions during developmental patterning.
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robustness of signaling gradient in drosophila wing imaginal disc
Discrete and Continuous Dynamical Systems-series B, 2011Co-Authors: Jinzhi Lei, Frederic Y M Wan, Arthur D Lander, Qing NieAbstract:Quasi-stable gradients of signaling protein molecules (known as Morphogens or ligands) bound to cell receptors are known to be responsible for differential cell signaling and gene expressions. From these follow different stable cell fates and visually patterned tissues in biological development. Recent studies have shown that the relevant basic biological processes yield gradients that are sensitive to small changes in system characteristics (such as expression level of Morphogens or receptors) or environmental conditions (such as temperature changes). Additional biological activities must play an important role in the high level of robustness observed in embryonic patterning for example. It is natural to attribute observed robustness to various type of feedback control mechanisms. However, our own simulation studies have shown that feedback control is neither necessary nor sufficient for robustness of the Morphogen decapentaplegic (Dpp) gradient in wing imaginal disc of Drosophilas. Furthermore, robustness can be achieved by substantial binding of the signaling Morphogen Dpp with nonsignaling cell surface bound molecules (such as heparan sulfate proteoglygans) and degrading the resulting complexes at a sufficiently rapid rate. The present work provides a theoretical basis for the results of our numerical simulation studies.
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do Morphogen gradients arise by diffusion
Developmental Biology, 2002Co-Authors: Arthur D Lander, Qing Nie, Frederic Y M WanAbstract:Many patterns of cell and tissue organization are specified during development by gradients of Morphogens, substances that assign different cell fates at different concentrations. Gradients form by Morphogen transport from a localized site, but whether this occurs by simple diffusion or by more elaborate mechanisms is unclear. We attempt to resolve this controversy by analyzing recent data in ways that appropriately capture the complexity of systems in which transport, receptor interaction, endo- and exocytosis, and degradation occur together. We find that diffusive mechanisms of Morphogen transport are much more plausible-and nondiffusive mechanisms much less plausible-than has generally been argued. Moreover, we show that a class of experiments, endocytic blockade, thought to effectively distinguish between diffusive and nondiffusive transport models actually fails to draw useful distinctions.
Arthur D Lander - One of the best experts on this subject based on the ideXlab platform.
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free extracellular diffusion creates the dpp Morphogen gradient of the drosophila wing disc
Current Biology, 2012Co-Authors: Shaohua Zhou, Qing Nie, Jeffrey L Suhalim, Michelle A Digman, Enrico Gratton, Arthur D LanderAbstract:Summary Background 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. Results 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. Conclusions 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.
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robustness of signaling gradient in drosophila wing imaginal disc
Discrete and Continuous Dynamical Systems-series B, 2011Co-Authors: Jinzhi Lei, Frederic Y M Wan, Arthur D Lander, Qing NieAbstract:Quasi-stable gradients of signaling protein molecules (known as Morphogens or ligands) bound to cell receptors are known to be responsible for differential cell signaling and gene expressions. From these follow different stable cell fates and visually patterned tissues in biological development. Recent studies have shown that the relevant basic biological processes yield gradients that are sensitive to small changes in system characteristics (such as expression level of Morphogens or receptors) or environmental conditions (such as temperature changes). Additional biological activities must play an important role in the high level of robustness observed in embryonic patterning for example. It is natural to attribute observed robustness to various type of feedback control mechanisms. However, our own simulation studies have shown that feedback control is neither necessary nor sufficient for robustness of the Morphogen decapentaplegic (Dpp) gradient in wing imaginal disc of Drosophilas. Furthermore, robustness can be achieved by substantial binding of the signaling Morphogen Dpp with nonsignaling cell surface bound molecules (such as heparan sulfate proteoglygans) and degrading the resulting complexes at a sufficiently rapid rate. The present work provides a theoretical basis for the results of our numerical simulation studies.
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morpheus unbound reimagining the Morphogen gradient
Cell, 2007Co-Authors: Arthur D LanderAbstract:The theory that the spatial organization of cell fate is orchestrated by gradients of diffusing molecules was a major contribution to 20th 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.
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do Morphogen gradients arise by diffusion
Developmental Biology, 2002Co-Authors: Arthur D Lander, Qing Nie, Frederic Y M WanAbstract:Many patterns of cell and tissue organization are specified during development by gradients of Morphogens, substances that assign different cell fates at different concentrations. Gradients form by Morphogen transport from a localized site, but whether this occurs by simple diffusion or by more elaborate mechanisms is unclear. We attempt to resolve this controversy by analyzing recent data in ways that appropriately capture the complexity of systems in which transport, receptor interaction, endo- and exocytosis, and degradation occur together. We find that diffusive mechanisms of Morphogen transport are much more plausible-and nondiffusive mechanisms much less plausible-than has generally been argued. Moreover, we show that a class of experiments, endocytic blockade, thought to effectively distinguish between diffusive and nondiffusive transport models actually fails to draw useful distinctions.
Xinhua Lin - One of the best experts on this subject based on the ideXlab platform.
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Shaping Morphogen Gradients by Proteoglycans
Cold Spring Harbor Perspectives in Biology, 2009Co-Authors: Dong Yan, Xinhua LinAbstract:During development, secreted Morphogens such as Wnt, Hedgehog (Hh), and BMP emit from their producing cells in a Morphogenetic field, and specify different cell fates in a direct concentration-dependent manner. Understanding how Morphogens form their concentration gradients to pattern tissues has been a central issue in developmental biology. Various experimental studies from Drosophila have led to several models to explain the formation of Morphogen gradients. Over the past decade, one of the main findings in this field is the characterization of heparan sulfate proteoglycan (HSPG) as an essential regulator for Morphogen gradient formation. Genetic and cell biological studies have showed that HSPGs can regulate Morphogen activities at various steps including control of Morphogen movement, signaling, and intracellular trafficking. Here, we review these data, highlighting recent findings that reveal mechanistic roles of HSPGs in controlling Morphogen gradient formation.
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distinct and collaborative roles of drosophila ext family proteins in Morphogen signalling and gradient formation
Development, 2004Co-Authors: Chun Han, Xinhua Lin, Tatyana Y Belenkaya, Marat Khodoun, Miyuki Tauchi, Xinda LinAbstract:Heparan sulfate proteoglycans (HSPG) have been implicated in regulating the signalling activities of secreted Morphogen molecules including Wingless (Wg), Hedgehog (Hh) and Decapentaplegic (Dpp). HSPG consists of a protein core to which heparan sulfate (HS) glycosaminoglycan (GAG) chains are attached. The formation of HS GAG chains is catalyzed by glycosyltransferases encoded by members of the EXT family of putative tumor suppressors linked to hereditary multiple exostoses. Previous studies in Drosophila demonstrated that tout-velu (ttv), the Drosophila EXT1, is required for Hh movement. However, the functions of other EXT family members are unknown. We have identified and isolated the other two members of the Drosophila EXT family genes, which are named sister of tout-velu (sotv) and brother of tout-velu (botv), and encode Drosophila homologues of vertebrate EXT2 and EXT-like 3 (EXTL3), respectively. We show that both Hh and Dpp signalling activities, as well as their Morphogen distributions, are defective in cells mutant for ttv, sotv or botv in the wing disc. Surprisingly, although Wg Morphogen distribution is abnormal in ttv, sotv and botv, Wg signalling is only defective in botv mutants or ttv-sotv double mutants, and not in ttv nor sotv alone, suggesting that Ttv and Sotv are redundant in Wg signalling. We demonstrate further that Ttv and Sotv form a complex and are co-localized in vivo. Our results, along with previous studies on Ttv, provide evidence that all three Drosophila EXT proteins are required for the biosynthesis of HSPGs, and for the gradient formation of the Wg, Hh and Dpp Morphogens. Our results also suggest that HSPGs have two distinct roles in Wg Morphogen distribution and signalling.
James Briscoe - One of the best experts on this subject based on the ideXlab platform.
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intrinsic noise profoundly alters the dynamics and steady state of Morphogen controlled bistable genetic switches
PLOS Computational Biology, 2016Co-Authors: Ruben Perezcarrasco, James Briscoe, Pilar Guerrero, Karen M PageAbstract:During tissue development, patterns of gene expression determine the spatial arrangement of cell types. In many cases, gradients of secreted signalling molecules—Morphogens—guide this process by controlling downstream transcriptional networks. A mechanism commonly used in these networks to convert the continuous information provided by the gradient into discrete transitions between adjacent cell types is the genetic toggle switch, composed of cross-repressing transcriptional determinants. Previous analyses have emphasised the steady state output of these mechanisms. Here, we explore the dynamics of the toggle switch and use exact numerical simulations of the kinetic reactions, the corresponding Chemical Langevin Equation, and Minimum Action Path theory to establish a framework for studying the effect of gene expression noise on patterning time and boundary position. This provides insight into the time scale, gene expression trajectories and directionality of stochastic switching events between cell states. Taking gene expression noise into account predicts that the final boundary position of a Morphogen-induced toggle switch, although robust to changes in the details of the noise, is distinct from that of the deterministic system. Moreover, the dramatic increase in patterning time close to the boundary predicted from the deterministic case is substantially reduced. The resulting stochastic switching introduces differences in patterning time along the Morphogen gradient that result in a patterning wave propagating away from the Morphogen source with a velocity determined by the intrinsic noise. The wave sharpens and slows as it advances and may never reach steady state in a biologically relevant time. This could explain experimentally observed dynamics of pattern formation. Together the analysis reveals the importance of dynamical transients for understanding Morphogen-driven transcriptional networks and indicates that gene expression noise can qualitatively alter developmental patterning.
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gene regulatory logic for reading the sonic hedgehog signaling gradient in the vertebrate neural tube
Cell, 2012Co-Authors: Nikolaos Balaskas, James Briscoe, A Ribeiro, Jasmina Panovska, Eric Dessaud, Noriaki Sasai, Karen M Page, Vanessa RibesAbstract:SUMMARY Secreted signals, known as Morphogens, provide the positional information that organizes gene expression and cellular differentiation in many developing tissues. In the vertebrate neural tube, Sonic Hedgehog (Shh) acts as a Morphogen to control the pattern of neuronal subtype specification. Using an in vivo reporter of Shh signaling, mouse genetics, and systems modeling, we show that a spatially and temporally changing gradient of Shh signaling isinterpretedbytheregulatorylogicofadownstream transcriptional network. The design of the network, which links three transcription factors to Shh signaling, is responsible for differential spatial and temporal gene expression. In addition, the network renders cells insensitive to fluctuations in signaling and confers hysteresis—memory of the signal. Our findings reveal that Morphogen interpretation is an emergent property of the architecture of a transcriptional network that provides robustness and reliability to tissue patterning.
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dynamic assignment and maintenance of positional identity in the ventral neural tube by the Morphogen sonic hedgehog
PLOS Biology, 2010Co-Authors: Eric Dessaud, Anna Kicheva, James Briscoe, Nikolaos Balaskas, Vanessa Ribes, Lin Lin Yang, Bennett G Novitch, Alessandra Pierani, Noriaki SasaiAbstract:Morphogens are secreted signalling molecules that act in a graded manner to control the pattern of cellular differentiation in developing tissues. An example is Sonic hedgehog (Shh), which acts in several developing vertebrate tissues, including the central nervous system, to provide positional information during embryonic patterning. Here we address how Shh signalling assigns the positional identities of distinct neuronal subtype progenitors throughout the ventral neural tube. Assays of intracellular signal transduction and gene expression indicate that the duration as well as level of signalling is critical for Morphogen interpretation. Progenitors of the ventral neuronal subtypes are established sequentially, with progressively more ventral identities requiring correspondingly higher levels and longer periods of Shh signalling. Moreover, cells remain sensitive to changes in Shh signalling for an extended time, reverting to antecedent identities if signalling levels fall below a threshold. Thus, the duration of signalling is important not only for the assignment but also for the refinement and maintenance of positional identity. Together the data suggest a dynamic model for ventral neural tube patterning in which positional information corresponds to the time integral of Shh signalling. This suggests an alternative to conventional models of Morphogen action that rely solely on the level of signalling.
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Morphogens and the control of cell proliferation and patterning in the spinal cord
Cell Cycle, 2007Co-Authors: Fausto Ulloa, James BriscoeAbstract:The development of animal embryos depends on accurate coordination of the growth and specification of precursor cells. Morphogens, extracellular signals that act at a distance to control cell fate, are crucial in the patterning of embryonic tissues. One of the most extensively studied examples of a Morphogen patterned tissue is the developing vertebrate spinal cord. The distribution of distinct neuronal subtypes along the dorsoventral (DV) axis of the spinal cord is determined by counteracting gradients of long-range signals. Wnt and BMP signals promote dorsal identities, while Shh signaling induces ventral identities. Simultaneous to their specification, neural progenitors proliferate, facilitating the growth of the neural tube. In this review we discuss evidence indicating that the signals governing progenitor specification also control proliferation and survival of progenitor cells. Moreover, evidence of reciprocal transcriptional interactions and cross-talk between the signaling pathways has emerged f...
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The interpretation of Morphogen gradients.
Development, 2006Co-Authors: Hilary L. Ashe, James BriscoeAbstract:Morphogens act as graded positional cues that control cell fate specification in many developing tissues. This concept, in which a signalling gradient regulates differential gene expression in a concentration-dependent manner, provides a basis for understanding many patterning processes. It also raises several mechanistic issues, such as how responding cells perceive and interpret the concentration-dependent information provided by a Morphogen to generate precise patterns of gene expression and cell differentiation in developing tissues. Here, we review recent work on the molecular features of Morphogen signalling that facilitate the interpretation of graded signals and attempt to identify some emerging common principles.
Konrad Basler - One of the best experts on this subject based on the ideXlab platform.
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Regulation of Organ Growth by Morphogen Gradients
Cold Spring Harbor Perspectives in Biology, 2009Co-Authors: Gerald Schwank, Konrad BaslerAbstract:Morphogen gradients play a fundamental role in organ patterning and organ growth. Unlike their role in patterning, their function in regulating the growth and the size of organs is poorly understood. How and why do Morphogen gradients exert their mitogenic effects to generate uniform proliferation in developing organs, and by what means can Morphogens impinge on the final size of organs? The decapentaplegic (Dpp) gradient in the Drosophila wing imaginal disc has emerged as a suitable and established system to study organ growth. Here, we review models and recent findings that attempt to address how the Dpp Morphogen contributes to uniform proliferation of cells, and how it may regulate the final size of wing discs.
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reggie 1 flotillin 2 promotes secretion of the long range signalling forms of wingless and hedgehog in drosophila
The EMBO Journal, 2008Co-Authors: Vladimir L Katanaev, Gonzalo P Solis, George Hausmann, Silke Buestorf, Natalya Katanayeva, Yvonne Schrock, Claudia A O Stuermer, Konrad BaslerAbstract:The lipid-modified Morphogens Wnt and Hedgehog diffuse poorly in isolation yet can spread over long distances in vivo, predicting existence of two distinct forms of these mophogens. The first is poorly mobile and activates short-range target genes. The second is specifically packed for efficient spreading to induce long-range targets. Subcellular mechanisms involved in the discriminative secretion of these two forms remain elusive. Wnt and Hedgehog can associate with membrane microdomains, but the function of this association was unknown. Here we show that a major protein component of membrane microdomains, reggie-1/flotillin-2, plays important roles in secretion and spreading of Wnt and Hedgehog in Drosophila. Reggie-1 loss-of-function results in reduced spreading of the Morphogens, while its overexpression stimulates secretion of Wnt and Hedgehog and expands their diffusion. The resulting changes in the Morphogen gradients differently affect the short- and long-range targets. In its action reggie-1 appears specific for Wnt and Hedgehog. These data suggest that reggie-1 is an important component of the Wnt and Hedgehog secretion pathway dedicated to formation of the mobile pool of these Morphogens.
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the decapentaplegic Morphogen gradient from pattern formation to growth regulation
Nature Reviews Genetics, 2007Co-Authors: Markus Affolter, Konrad BaslerAbstract:Morphogens have been linked to numerous developmental processes, including organ patterning and the control of organ size. Here we review how different experimental approaches have led to an unprecedented level of molecular knowledge about the patterning role of the Drosophila melanogaster Morphogen Decapentaplegic (DPP, the homologue of vertebrate bone Morphogenetic protein, or BMP), the first validated secreted Morphogen. In addition, we discuss how little is known about the role of the DPP Morphogen in the control of organ growth and organ size. Continued efforts to elucidate the role of DPP in D. melanogaster is likely to shed light on this fundamental question in the near future.
