The Experts below are selected from a list of 15525 Experts worldwide ranked by ideXlab platform
Karen M Page - 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.
Anatoly B Kolomeisky - One of the best experts on this subject based on the ideXlab platform.
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Discrete-State Stochastic Modeling of Morphogen Gradient Formation
Methods in molecular biology (Clifton N.J.), 2018Co-Authors: Hamid Teimouri, Anatoly B KolomeiskyAbstract:In biological development, positional information required for pattern formation is carried by the gradients of special signaling molecules, which are called Morphogens. It is well known that the establishment of the morphogen gradients is a result of complex physical-chemical processes that involve diffusion, degradation of locally produced signaling molecules, and other biochemical reactions. Here we describe a recently developed discrete-state stochastic theoretical method to explain the formation of morphogen gradients in complex cellular environment.
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Mechanisms of the formation of biological signaling profiles
Journal of Physics A, 2016Co-Authors: Hamid Teimouri, Anatoly B KolomeiskyAbstract:The formation and growth of multi-cellular organisms and tissues from several genetically identical embryo cells is one of the most fundamental natural phenomena. These processes are stimulated and governed by multiple biological signaling molecules, which are also called Morphogens. Embryo cells are able to read and pass genetic information by measuring the non-uniform concentration profiles of signaling molecules. It is widely believed that the establishment of concentration profiles of Morphogens, commonly referred as morphogen gradients, is a result of complex biophysical and biochemical processes that might involve diffusion and degradation of locally produced signaling molecules. In this review, we discuss various theoretical aspects of the mechanisms for morphogen gradient formation, including stationary and transient dynamics, the effect of source delocalization, diffusion, different degradation mechanisms, and the role of spatial dimensions. Theoretical predictions are compared with experimental observations. In addition, we analyze the potential alternative mechanisms of the delivery of biological signals in embryo cells and tissues. Current challenges in understanding the mechanisms of morphogen gradients and future directions are also discussed.
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Development of Morphogen Gradients with Spatially Varying Degradation Rates
Journal of Physical Chemistry B, 2016Co-Authors: Hamid Teimouri, Behnaz Bozorgui, Anatoly B KolomeiskyAbstract:Successful biological development via spatial and temporal regulations of cell differentiation relies on the action of multiple signaling molecules that are known as Morphogens. It is now well established that biological signaling molecules create nonuniform concentration profiles, called morphogen gradients, that activate different genes, leading to patterning in the developing organisms. The current view of the formation of morphogen gradients is that it is a result of complex reaction–diffusion processes that include production, diffusion, and degradation of signaling molecules. Recent studies also suggest that the degradation of Morphogens is a critically important step in the whole process. We develop a theoretical model that allows us to investigate the role of a spatially varying degradation in the formation of morphogen gradients. Our analysis shows that the spatial inhomogeneities in degradation might strongly influence the dynamics of formation of signaling profiles. Physical–chemical mechanisms...
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Theoretical analysis of degradation mechanisms in the formation of morphogen gradients.
Journal of Chemical Physics, 2015Co-Authors: Behnaz Bozorgui, Hamid Teimouri, Anatoly B KolomeiskyAbstract:Fundamental biological processes of development of tissues and organs in multicellular organisms are governed by various signaling molecules, which are called Morphogens. It is known that spatial and temporal variations in the concentration profiles of signaling molecules, which are frequently referred as morphogen gradients, lead to a cell differentiation via activating specific genes in a concentration-dependent manner. It is widely accepted that the establishment of the morphogen gradients involves multiple biochemical reactions and diffusion processes. One of the critical elements in the formation of morphogen gradients is a degradation of signaling molecules. We develop a new theoretical approach that provides a comprehensive description of the degradation mechanisms. It is based on the idea that the degradation works as an effective potential that drives the signaling molecules away from the source region. Utilizing the method of first-passage processes, the dynamics of the formation of morphogen gradients for various degradation mechanisms is explicitly evaluated. It is found that linear degradation processes lead to a dynamic behavior specified by times to form the morphogen gradients that depend linearly on the distance from the source. This is because the effective potential due to the degradation is quite strong. At the same time, nonlinear degradation mechanisms yield a quadratic scaling in the morphogen gradients formation times since the effective potentials are much weaker. Physical-chemical explanations of these phenomena are presented.
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The role of source delocalization in the development of morphogen gradients.
Physical Biology, 2015Co-Authors: Hamid Teimouri, Anatoly B KolomeiskyAbstract:Successful biological development via spatial regulation of cell differentiation relies on the action of multiple signaling molecules that are known as Morphogens. It is now well-established that signaling molecules create non-uniform concentration profiles, morphogen gradients, that activate different genes, leading to patterning in the developing embryos. The current view of the formation of morphogen gradients is that it is a result of complex reaction-diffusion processes that include the strongly localized production, diffusion and uniform degradation of signaling molecules. However, multiple experimental studies also suggest that the production of morphogen in many cases is delocalized. We develop a theoretical method that allows us to investigate the role of the delocalization in the formation of morphogen gradients. The approach is based on discrete-state stochastic models that can be solved exactly for arbitrary production lengths and production rates of morphogen molecules. Our analysis shows that the delocalization might have a strong effect on mechanisms of the morphogen gradient formation. The physical origin of this effect is discussed.
Marc Tessierlavigne - One of the best experts on this subject based on the ideXlab platform.
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the hedgehog tgf β bmp and wnt families of Morphogens in axon guidance
Advances in Experimental Medicine and Biology, 2007Co-Authors: Frederic Charron, Marc TessierlavigneAbstract:During embryonic development, Morphogens act as graded positional cues to dictate cell fate specification and tissue patterning. Recent findings indicate that morphogen gradients also serve to guide axonal pathfinding during development of the nervous system. These findings challenge our previous notions about Morphogens and axon guidance molecules and suggest that these proteins, rather than having sharply divergent functions, act more globally to provide graded positional information that can be interpreted by responding cells either to specify cell fate or to direct axonal pathfinding. This chapter presents the roles identified for members of three prominent morphogen families—the Hedgehog, Wnt and TGF-β/BMP families—in axon guidance, and discusses potential implications for the molecular mechanisms underlying their guidance functions.
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novel brain wiring functions for classical Morphogens a role as graded positional cues in axon guidance
Development, 2005Co-Authors: Frederic Charron, Marc TessierlavigneAbstract:During embryonic development, Morphogens act as graded positional cues to dictate cell fate specification and tissue patterning. Recent findings indicate that morphogen gradients also serve to guide axonal pathfinding during development of the nervous system. These findings challenge our previous notions about Morphogens and axon guidance molecules, and suggest that these proteins, rather than having sharply divergent functions, act more globally to provide graded positional information that can be interpreted by responding cells either to specify cell fate or to direct axonal pathfinding. This review presents the roles identified for members of three prominent morphogen families – the Hedgehog, Wnt and TGFβ/BMP families– in axon guidance, and discusses potential implications for the molecular mechanisms underlying their guidance functions.
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mammalian brain morphogenesis and midline axon guidance require heparan sulfate
Science, 2003Co-Authors: Masaru Inatani, Marc Tessierlavigne, Fumitoshi Irie, Andrew S Plump, Yu YamaguchiAbstract:Heparan sulfate (HS) is required for morphogen signaling during Drosophila pattern formation, but little is known about its physiological importance in mammalian development. To define the developmental role of HS in mammalian species, we conditionally disrupted the HS-polymerizing enzyme EXT1 in the embryonic mouse brain. The EXT1-null brain exhibited patterning defects that are composites of those caused by mutations of multiple HS-binding Morphogens. Furthermore, the EXT1-null brain displayed severe guidance errors in major commissural tracts, revealing a pivotal role of HS in midline axon guidance. These findings demonstrate that HS is essential for mammalian brain development.
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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Temporal dynamics of patterning by morphogen gradients
Current Opinion in Genetics & Development, 2009Co-Authors: Eva Kutejova, James Briscoe, Anna KichevaAbstract:Morphogens act as graded positional cues to control cell fate specification in many developing tissues. This concept, in which a signaling gradient regulates differential gene expression in a concentration-dependent manner, has received considerable experimental support. Nevertheless, several recent studies have challenged the straightforward model of morphogen activity. In particular, the observation that pattern formation is a dynamic process has raised questions about the influence of time on morphogen activity. Here we propose that the spatiotemporal dynamics of the cellular response to a morphogen gradient depend on a combination of temporal alterations to the morphogen gradient itself, the dynamics of its signal transduction and downstream interactions between target genes.
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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.
Steven Falconer - One of the best experts on this subject based on the ideXlab platform.
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nonlinear degradation enhanced transport of Morphogens performing subdiffusion
Physical Review E, 2014Co-Authors: Sergei Fedotov, Steven FalconerAbstract:We study a morphogen gradient formation under nonlinear degradation and subdiffusive transport. In the long-time limit, we obtain the nonlinear effect of degradation-enhanced diffusion, resulting from the interaction of non-Markovian subdiffusive transport with a nonlinear reaction. We find the stationary profile of power-law type, which has implications for robustness, with the shape of the profile being controlled by the anomalous exponent. Far away from the source of Morphogens, any changes in the rate of production are not felt.
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Self enhanced degradation and subdiffusion of Morphogens
arXiv: Statistical Mechanics, 2013Co-Authors: Sergei Fedotov, Steven FalconerAbstract:We study a nonlinear degradation of Morphogens performing subdiffusion. We discuss the interaction of subdiffusion with a nonlinear degradation, leading to a nonlinear diffusion in the long time limit. We find that in the subdiffusive case, a self enhanced degradation of morphogen leads directly to a degradation enhanced diffusion. We obtain the stationary profile of power-law type, which has implications for robustness, with the shape of the profile being controlled by the anomalous exponent. Far away from the source of Morphogens, any changes in rate of production are not felt.