Limits...
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.

Show MeSH

Related in: MedlinePlus

Refractoriness to Wg is conferred by the Notch target gene cut.(A) Mature cut6 mutant wing disc showing co-expression of the proteins Senseless, Sens, (in blue) and Wg (in red) in boundary cells. (B) Clones of cells lacking cut activity marked by the absence of GFP (red). Sens (in blue) starts to be expressed in boundary cells. (C) Mature cut6 mutant wing disc that expresses the intracellular domain of Notch (Nintra) under dppGal4 control. Wg protein expression is shown in red and Sens protein expression in blue. (D) Mature wing disc that expresses Cut and GFP (green) under dppGal4 control. Note the loss of Sens expression (blue) and ectopic expression of Wg (red) in non-boundary cells. (A'–D') In silico counterparts of the results shown in (A–D).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC1904254&req=5

pone-0000602-g004: Refractoriness to Wg is conferred by the Notch target gene cut.(A) Mature cut6 mutant wing disc showing co-expression of the proteins Senseless, Sens, (in blue) and Wg (in red) in boundary cells. (B) Clones of cells lacking cut activity marked by the absence of GFP (red). Sens (in blue) starts to be expressed in boundary cells. (C) Mature cut6 mutant wing disc that expresses the intracellular domain of Notch (Nintra) under dppGal4 control. Wg protein expression is shown in red and Sens protein expression in blue. (D) Mature wing disc that expresses Cut and GFP (green) under dppGal4 control. Note the loss of Sens expression (blue) and ectopic expression of Wg (red) in non-boundary cells. (A'–D') In silico counterparts of the results shown in (A–D).

Mentions: High levels of Notch activity induce expression of the homeobox gene cut in boundary cells [10] and Cut has been previously shown to be required to repress Delta and Serrate expression in these cells [9]. We then examined whether Cut mediates the activity of Notch in inhibiting the expression of other Wg target genes. In the absence of Cut activity, either in a homozygous mutant background or in clones of mutant cells, boundary cells start expressing genes regulated by the Wg signal (Figures 4A and 4B, and Figure S1), and ectopic Notch activation in non-boundary cells is now unable to repress Wg target gene expression (Figure 4C; compare with Figure 3C; see also Figure S1). Note that Notch, in this case, causes ectopic expression of Wg, which induces target gene expression in both Wg-expressing and non-expressing cells. Finally, forced expression of Cut in non-boundary cells represses the expression of Wg target genes (Figure 4D and Figure S1). Taken together, these results indicate that Cut is not only required but also sufficient to inhibit Wg target gene expression in boundary cells downstream of Notch.


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)

Refractoriness to Wg is conferred by the Notch target gene cut.(A) Mature cut6 mutant wing disc showing co-expression of the proteins Senseless, Sens, (in blue) and Wg (in red) in boundary cells. (B) Clones of cells lacking cut activity marked by the absence of GFP (red). Sens (in blue) starts to be expressed in boundary cells. (C) Mature cut6 mutant wing disc that expresses the intracellular domain of Notch (Nintra) under dppGal4 control. Wg protein expression is shown in red and Sens protein expression in blue. (D) Mature wing disc that expresses Cut and GFP (green) under dppGal4 control. Note the loss of Sens expression (blue) and ectopic expression of Wg (red) in non-boundary cells. (A'–D') In silico counterparts of the results shown in (A–D).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1904254&req=5

pone-0000602-g004: Refractoriness to Wg is conferred by the Notch target gene cut.(A) Mature cut6 mutant wing disc showing co-expression of the proteins Senseless, Sens, (in blue) and Wg (in red) in boundary cells. (B) Clones of cells lacking cut activity marked by the absence of GFP (red). Sens (in blue) starts to be expressed in boundary cells. (C) Mature cut6 mutant wing disc that expresses the intracellular domain of Notch (Nintra) under dppGal4 control. Wg protein expression is shown in red and Sens protein expression in blue. (D) Mature wing disc that expresses Cut and GFP (green) under dppGal4 control. Note the loss of Sens expression (blue) and ectopic expression of Wg (red) in non-boundary cells. (A'–D') In silico counterparts of the results shown in (A–D).
Mentions: High levels of Notch activity induce expression of the homeobox gene cut in boundary cells [10] and Cut has been previously shown to be required to repress Delta and Serrate expression in these cells [9]. We then examined whether Cut mediates the activity of Notch in inhibiting the expression of other Wg target genes. In the absence of Cut activity, either in a homozygous mutant background or in clones of mutant cells, boundary cells start expressing genes regulated by the Wg signal (Figures 4A and 4B, and Figure S1), and ectopic Notch activation in non-boundary cells is now unable to repress Wg target gene expression (Figure 4C; compare with Figure 3C; see also Figure S1). Note that Notch, in this case, causes ectopic expression of Wg, which induces target gene expression in both Wg-expressing and non-expressing cells. Finally, forced expression of Cut in non-boundary cells represses the expression of Wg target genes (Figure 4D and Figure S1). Taken together, these results indicate that Cut is not only required but also sufficient to inhibit Wg target gene expression in boundary cells downstream of Notch.

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
Related in: MedlinePlus