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Robustness and stability of the gene regulatory network involved in DV boundary formation in the Drosophila wing.

Buceta J, Herranz H, Canela-Xandri O, Reigada R, Sagués F, Milán M - PLoS ONE (2007)

Bottom Line: By means of a Systems Biology approach that combines mathematical modeling and both in silico and in vivo experiments in the Drosophila wing primordium, we modeled and tested this regulatory network and present evidence that a novel property, namely refractoriness to the Wingless signaling molecule, is required in boundary cells for the formation of a stable dorsal-ventral boundary.This new property has been validated in vivo, promotes mutually exclusive domains of Notch and Wingless activities and confers stability to the dorsal-ventral boundary.A robustness analysis of the regulatory network complements our results and ensures its biological plausibility.

View Article: PubMed Central - PubMed

Affiliation: Centre especial de Recerca en Química Teòrica (CeRQT), Parc Científic de Barcelona, Barcelona, Spain. jbuceta@pcb.ub.es

ABSTRACT
Gene regulatory networks have been conserved during evolution. The Drosophila wing and the vertebrate hindbrain share the gene network involved in the establishment of the boundary between dorsal and ventral compartments in the wing and adjacent rhombomeres in the hindbrain. A positive feedback-loop between boundary and non-boundary cells and mediated by the activities of Notch and Wingless/Wnt-1 leads to the establishment of a Notch dependent organizer at the boundary. By means of a Systems Biology approach that combines mathematical modeling and both in silico and in vivo experiments in the Drosophila wing primordium, we modeled and tested this regulatory network and present evidence that a novel property, namely refractoriness to the Wingless signaling molecule, is required in boundary cells for the formation of a stable dorsal-ventral boundary. This new property has been validated in vivo, promotes mutually exclusive domains of Notch and Wingless activities and confers stability to the dorsal-ventral boundary. A robustness analysis of the regulatory network complements our results and ensures its biological plausibility.

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In silico testing of the gene regulatory network: refractoriness to Wg in boundary cells renders stability to the DV regulatory network.(A) Regulatory network for the formation of the DV boundary. Positive and negative regulations are coded with green and red colors, respectively. Color intensity in positive regulations indicates, qualitatively, the strength of expression levels (the lighter the weaker). The green-red dashed line that ends with a rhombic arrowhead indicates that receptor-ligand dynamics may lead to either positive or negative regulation: Notch-ligand binding in the same cell (intra) or in adjacent neighboring cells (inter) lead, respectively, to titration (sequestering effects) or activation of Notch. Activated Notch induces ligand and receptor expression at low levels, thus closing a positive feedback loop that maintains each other's expression at early stages of wing development. Note that Notch has an additional autonomous off-network regulation. Increased Notch activity induces expression of Wg and Cut. The latter represses Ser and Dl. (B) Evolution of Wg (red) expression levels, Notch activated (black), and Cut (green) in boundary cells as a function of time. The boundary is initially established but cannot be maintained (see text). (C) Evolution of Wg (red) expression, Notch activated (black), and Cut (green) levels in boundary cells as a function of time in a scenario in which refractoriness to Wg has been taken into account in boundary cells (see text). Note stable activation of Notch and expression of Wg and Cut in this case, when compared to (B).
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pone-0000602-g002: In silico testing of the gene regulatory network: refractoriness to Wg in boundary cells renders stability to the DV regulatory network.(A) Regulatory network for the formation of the DV boundary. Positive and negative regulations are coded with green and red colors, respectively. Color intensity in positive regulations indicates, qualitatively, the strength of expression levels (the lighter the weaker). The green-red dashed line that ends with a rhombic arrowhead indicates that receptor-ligand dynamics may lead to either positive or negative regulation: Notch-ligand binding in the same cell (intra) or in adjacent neighboring cells (inter) lead, respectively, to titration (sequestering effects) or activation of Notch. Activated Notch induces ligand and receptor expression at low levels, thus closing a positive feedback loop that maintains each other's expression at early stages of wing development. Note that Notch has an additional autonomous off-network regulation. Increased Notch activity induces expression of Wg and Cut. The latter represses Ser and Dl. (B) Evolution of Wg (red) expression levels, Notch activated (black), and Cut (green) in boundary cells as a function of time. The boundary is initially established but cannot be maintained (see text). (C) Evolution of Wg (red) expression, Notch activated (black), and Cut (green) levels in boundary cells as a function of time in a scenario in which refractoriness to Wg has been taken into account in boundary cells (see text). Note stable activation of Notch and expression of Wg and Cut in this case, when compared to (B).

Mentions: On the basis of the aforementioned regulatory interactions, we aimed to revise, model and test the network that drives the establishment and maintenance of the DV organizer (Figure 2A). Our approach took into account a reduced, yet realistic, set of elements and their regulatory relationships. The main features of the network are the following: activated Notch is the “conductor” for the establishment of the DV boundary. Notch can be signaled by the ligands Serrate or Delta. Given that at this stage of development there is no difference in the way the ligands signal to Notch, we did not consider any difference between ligands apart from their initial DV asymmetric expression (Serrate:dorsal and Delta:ventral). Nonetheless, in our modeling approach we distinguished between the two ligands to track how symmetric expression is obtained at flanking stripes of the boundary. Depending on the relative concentration of receptor and ligands in the same cell (intracellular interactions) and neighboring cells (intercellular interactions), ligands may lead or not to the activation of the receptor. In Figure 2A we stress the dichotomous role played by receptor-ligand interactions (either positive or negative regulation of Notch pathway). If the Notch receptor is activated, then the transcription-translation of its downstream genes starts. Downstream genes are expressed, or not, at appreciable levels depending on the degree of Notch activity. As activation increases, Notch and the ligands themselves are expressed, afterwards Wg and then Cut, as experimentally shown elsewhere [10], [32], [36]. This ordered sequence of expression as a function of Notch activity levels fixes an ordered sequence for the threshold values of the regulatory functions in our modeling approach. Independently of Notch activation, there is an autonomous off-network Notch transcription-translation dynamics that keeps the expression levels of the receptor to a basal level in wing cells. Once Wg is expressed, it exerts its aforementioned roles in the proposed regulatory network: induction of Notch ligand expression and down-regulation of the Notch pathway. On the other hand, Cut represses Delta and Serrate expression in boundary cells.


Robustness and stability of the gene regulatory network involved in DV boundary formation in the Drosophila wing.

Buceta J, Herranz H, Canela-Xandri O, Reigada R, Sagués F, Milán M - PLoS ONE (2007)

In silico testing of the gene regulatory network: refractoriness to Wg in boundary cells renders stability to the DV regulatory network.(A) Regulatory network for the formation of the DV boundary. Positive and negative regulations are coded with green and red colors, respectively. Color intensity in positive regulations indicates, qualitatively, the strength of expression levels (the lighter the weaker). The green-red dashed line that ends with a rhombic arrowhead indicates that receptor-ligand dynamics may lead to either positive or negative regulation: Notch-ligand binding in the same cell (intra) or in adjacent neighboring cells (inter) lead, respectively, to titration (sequestering effects) or activation of Notch. Activated Notch induces ligand and receptor expression at low levels, thus closing a positive feedback loop that maintains each other's expression at early stages of wing development. Note that Notch has an additional autonomous off-network regulation. Increased Notch activity induces expression of Wg and Cut. The latter represses Ser and Dl. (B) Evolution of Wg (red) expression levels, Notch activated (black), and Cut (green) in boundary cells as a function of time. The boundary is initially established but cannot be maintained (see text). (C) Evolution of Wg (red) expression, Notch activated (black), and Cut (green) levels in boundary cells as a function of time in a scenario in which refractoriness to Wg has been taken into account in boundary cells (see text). Note stable activation of Notch and expression of Wg and Cut in this case, when compared to (B).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC1904254&req=5

pone-0000602-g002: In silico testing of the gene regulatory network: refractoriness to Wg in boundary cells renders stability to the DV regulatory network.(A) Regulatory network for the formation of the DV boundary. Positive and negative regulations are coded with green and red colors, respectively. Color intensity in positive regulations indicates, qualitatively, the strength of expression levels (the lighter the weaker). The green-red dashed line that ends with a rhombic arrowhead indicates that receptor-ligand dynamics may lead to either positive or negative regulation: Notch-ligand binding in the same cell (intra) or in adjacent neighboring cells (inter) lead, respectively, to titration (sequestering effects) or activation of Notch. Activated Notch induces ligand and receptor expression at low levels, thus closing a positive feedback loop that maintains each other's expression at early stages of wing development. Note that Notch has an additional autonomous off-network regulation. Increased Notch activity induces expression of Wg and Cut. The latter represses Ser and Dl. (B) Evolution of Wg (red) expression levels, Notch activated (black), and Cut (green) in boundary cells as a function of time. The boundary is initially established but cannot be maintained (see text). (C) Evolution of Wg (red) expression, Notch activated (black), and Cut (green) levels in boundary cells as a function of time in a scenario in which refractoriness to Wg has been taken into account in boundary cells (see text). Note stable activation of Notch and expression of Wg and Cut in this case, when compared to (B).
Mentions: On the basis of the aforementioned regulatory interactions, we aimed to revise, model and test the network that drives the establishment and maintenance of the DV organizer (Figure 2A). Our approach took into account a reduced, yet realistic, set of elements and their regulatory relationships. The main features of the network are the following: activated Notch is the “conductor” for the establishment of the DV boundary. Notch can be signaled by the ligands Serrate or Delta. Given that at this stage of development there is no difference in the way the ligands signal to Notch, we did not consider any difference between ligands apart from their initial DV asymmetric expression (Serrate:dorsal and Delta:ventral). Nonetheless, in our modeling approach we distinguished between the two ligands to track how symmetric expression is obtained at flanking stripes of the boundary. Depending on the relative concentration of receptor and ligands in the same cell (intracellular interactions) and neighboring cells (intercellular interactions), ligands may lead or not to the activation of the receptor. In Figure 2A we stress the dichotomous role played by receptor-ligand interactions (either positive or negative regulation of Notch pathway). If the Notch receptor is activated, then the transcription-translation of its downstream genes starts. Downstream genes are expressed, or not, at appreciable levels depending on the degree of Notch activity. As activation increases, Notch and the ligands themselves are expressed, afterwards Wg and then Cut, as experimentally shown elsewhere [10], [32], [36]. This ordered sequence of expression as a function of Notch activity levels fixes an ordered sequence for the threshold values of the regulatory functions in our modeling approach. Independently of Notch activation, there is an autonomous off-network Notch transcription-translation dynamics that keeps the expression levels of the receptor to a basal level in wing cells. Once Wg is expressed, it exerts its aforementioned roles in the proposed regulatory network: induction of Notch ligand expression and down-regulation of the Notch pathway. On the other hand, Cut represses Delta and Serrate expression in boundary cells.

Bottom Line: By means of a Systems Biology approach that combines mathematical modeling and both in silico and in vivo experiments in the Drosophila wing primordium, we modeled and tested this regulatory network and present evidence that a novel property, namely refractoriness to the Wingless signaling molecule, is required in boundary cells for the formation of a stable dorsal-ventral boundary.This new property has been validated in vivo, promotes mutually exclusive domains of Notch and Wingless activities and confers stability to the dorsal-ventral boundary.A robustness analysis of the regulatory network complements our results and ensures its biological plausibility.

View Article: PubMed Central - PubMed

Affiliation: Centre especial de Recerca en Química Teòrica (CeRQT), Parc Científic de Barcelona, Barcelona, Spain. jbuceta@pcb.ub.es

ABSTRACT
Gene regulatory networks have been conserved during evolution. The Drosophila wing and the vertebrate hindbrain share the gene network involved in the establishment of the boundary between dorsal and ventral compartments in the wing and adjacent rhombomeres in the hindbrain. A positive feedback-loop between boundary and non-boundary cells and mediated by the activities of Notch and Wingless/Wnt-1 leads to the establishment of a Notch dependent organizer at the boundary. By means of a Systems Biology approach that combines mathematical modeling and both in silico and in vivo experiments in the Drosophila wing primordium, we modeled and tested this regulatory network and present evidence that a novel property, namely refractoriness to the Wingless signaling molecule, is required in boundary cells for the formation of a stable dorsal-ventral boundary. This new property has been validated in vivo, promotes mutually exclusive domains of Notch and Wingless activities and confers stability to the dorsal-ventral boundary. A robustness analysis of the regulatory network complements our results and ensures its biological plausibility.

Show MeSH