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Mutual inactivation of Notch receptors and ligands facilitates developmental patterning.

Sprinzak D, Lakhanpal A, LeBon L, Garcia-Ojalvo J, Elowitz MB - PLoS Comput. Biol. (2011)

Bottom Line: It generally remains unclear, however, how this mutual inactivation and the resulting switching behavior can impact developmental patterning circuits.For lateral inhibition, we find that mutual inactivation speeds up patterning dynamics, relieves the need for cooperative regulatory interactions, and expands the range of parameter values that permit pattern formation, compared to canonical models.Together, these results provide a framework for analysis of more complex Notch-dependent developmental systems.

View Article: PubMed Central - PubMed

Affiliation: Howard Hughes Medical Institute, California Institute of Technology, Pasadena, California, USA.

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Related in: MedlinePlus

Mutual inactivation facilitates wing vein boundary formation.(A) Schematic of vein boundary formation. During vein formation a gradient in DSL production from the center of the vein (left, red) is converted into two sharply defined sidebands of Notch target expression (right, green). (B) Cartoon of the Bandpass regulatory mechanism, in which the boundary is determined by a transcription-level filter which determines the mapping from Notch activity to cell fate. Note that there is no feedback on the signaling system. (C) Cartoon of the Mutual Inactivation model regulatory mechanism, in which the level of Notch signaling directly determines the cell fate. Note again that there is no feedback on the signaling system. (D) Simulations of boundary formation. Top: DSL gradient profiles (three red curves) with varying slopes, chosen to generate side bands at a fixed position. Middle, bottom: Profiles of target reporter concentrations for the three slopes shown in the top panel for the MI model (middle) and the BP model (bottom). (E) Dependence of peak width on slope for the two models. In the MI model (top panel), peak width, w, remains small over a range of gradient slopes and strengths of the mutual inactivation interaction, . Here, smaller  corresponds to stronger cis-inhibition (See Eqns. 1–2). In the BP model (bottom panel) peak width depends on the gradient slope as well as on the bandpass steepness parameter, . Here, higher  corresponds to a steeper bandpass (see Eqn. 6 and Fig. S1). Note that for the BP model, DSL production profiles were shifted to lower levels (see Table S1) but maintained the same slopes compared to the profiles shown in (B, top). This made sure that the bandpass is in a functional regime in which Notch signaling varies linearly with position (e.g. as in Fig. S1B). See Table S1 for parameter values.
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pcbi-1002069-g002: Mutual inactivation facilitates wing vein boundary formation.(A) Schematic of vein boundary formation. During vein formation a gradient in DSL production from the center of the vein (left, red) is converted into two sharply defined sidebands of Notch target expression (right, green). (B) Cartoon of the Bandpass regulatory mechanism, in which the boundary is determined by a transcription-level filter which determines the mapping from Notch activity to cell fate. Note that there is no feedback on the signaling system. (C) Cartoon of the Mutual Inactivation model regulatory mechanism, in which the level of Notch signaling directly determines the cell fate. Note again that there is no feedback on the signaling system. (D) Simulations of boundary formation. Top: DSL gradient profiles (three red curves) with varying slopes, chosen to generate side bands at a fixed position. Middle, bottom: Profiles of target reporter concentrations for the three slopes shown in the top panel for the MI model (middle) and the BP model (bottom). (E) Dependence of peak width on slope for the two models. In the MI model (top panel), peak width, w, remains small over a range of gradient slopes and strengths of the mutual inactivation interaction, . Here, smaller corresponds to stronger cis-inhibition (See Eqns. 1–2). In the BP model (bottom panel) peak width depends on the gradient slope as well as on the bandpass steepness parameter, . Here, higher corresponds to a steeper bandpass (see Eqn. 6 and Fig. S1). Note that for the BP model, DSL production profiles were shifted to lower levels (see Table S1) but maintained the same slopes compared to the profiles shown in (B, top). This made sure that the bandpass is in a functional regime in which Notch signaling varies linearly with position (e.g. as in Fig. S1B). See Table S1 for parameter values.

Mentions: Wing vein formation in the developing fly is a classic model system for studying the generation of sharp boundaries. In the Drosophila wing, there are four longitudinal veins that include several rows of cells that are more compact and have darker pigmentation than intervein cells. The position of the wing veins in the wing imaginal disk is initiated by EGF signaling during the early stages of larva development [18]. The final form (position and width) of the wing veins is refined by several subsequent processes. Notch signaling has been shown to specifically control the sharpening of the boundary between pro-vein (the region competent to produce vein fates) and intervein regions in the wing disc [1], [2]. In this system, the Delta production rate is controlled by a gradient of veinless expression diminishing outward from the center of the pro-vein region (Fig. 2A, left). Notch signaling is observed in two sharply defined side-bands, which restrict further vein development to the region between them (Fig. 2A, right).


Mutual inactivation of Notch receptors and ligands facilitates developmental patterning.

Sprinzak D, Lakhanpal A, LeBon L, Garcia-Ojalvo J, Elowitz MB - PLoS Comput. Biol. (2011)

Mutual inactivation facilitates wing vein boundary formation.(A) Schematic of vein boundary formation. During vein formation a gradient in DSL production from the center of the vein (left, red) is converted into two sharply defined sidebands of Notch target expression (right, green). (B) Cartoon of the Bandpass regulatory mechanism, in which the boundary is determined by a transcription-level filter which determines the mapping from Notch activity to cell fate. Note that there is no feedback on the signaling system. (C) Cartoon of the Mutual Inactivation model regulatory mechanism, in which the level of Notch signaling directly determines the cell fate. Note again that there is no feedback on the signaling system. (D) Simulations of boundary formation. Top: DSL gradient profiles (three red curves) with varying slopes, chosen to generate side bands at a fixed position. Middle, bottom: Profiles of target reporter concentrations for the three slopes shown in the top panel for the MI model (middle) and the BP model (bottom). (E) Dependence of peak width on slope for the two models. In the MI model (top panel), peak width, w, remains small over a range of gradient slopes and strengths of the mutual inactivation interaction, . Here, smaller  corresponds to stronger cis-inhibition (See Eqns. 1–2). In the BP model (bottom panel) peak width depends on the gradient slope as well as on the bandpass steepness parameter, . Here, higher  corresponds to a steeper bandpass (see Eqn. 6 and Fig. S1). Note that for the BP model, DSL production profiles were shifted to lower levels (see Table S1) but maintained the same slopes compared to the profiles shown in (B, top). This made sure that the bandpass is in a functional regime in which Notch signaling varies linearly with position (e.g. as in Fig. S1B). See Table S1 for parameter values.
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Related In: Results  -  Collection

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pcbi-1002069-g002: Mutual inactivation facilitates wing vein boundary formation.(A) Schematic of vein boundary formation. During vein formation a gradient in DSL production from the center of the vein (left, red) is converted into two sharply defined sidebands of Notch target expression (right, green). (B) Cartoon of the Bandpass regulatory mechanism, in which the boundary is determined by a transcription-level filter which determines the mapping from Notch activity to cell fate. Note that there is no feedback on the signaling system. (C) Cartoon of the Mutual Inactivation model regulatory mechanism, in which the level of Notch signaling directly determines the cell fate. Note again that there is no feedback on the signaling system. (D) Simulations of boundary formation. Top: DSL gradient profiles (three red curves) with varying slopes, chosen to generate side bands at a fixed position. Middle, bottom: Profiles of target reporter concentrations for the three slopes shown in the top panel for the MI model (middle) and the BP model (bottom). (E) Dependence of peak width on slope for the two models. In the MI model (top panel), peak width, w, remains small over a range of gradient slopes and strengths of the mutual inactivation interaction, . Here, smaller corresponds to stronger cis-inhibition (See Eqns. 1–2). In the BP model (bottom panel) peak width depends on the gradient slope as well as on the bandpass steepness parameter, . Here, higher corresponds to a steeper bandpass (see Eqn. 6 and Fig. S1). Note that for the BP model, DSL production profiles were shifted to lower levels (see Table S1) but maintained the same slopes compared to the profiles shown in (B, top). This made sure that the bandpass is in a functional regime in which Notch signaling varies linearly with position (e.g. as in Fig. S1B). See Table S1 for parameter values.
Mentions: Wing vein formation in the developing fly is a classic model system for studying the generation of sharp boundaries. In the Drosophila wing, there are four longitudinal veins that include several rows of cells that are more compact and have darker pigmentation than intervein cells. The position of the wing veins in the wing imaginal disk is initiated by EGF signaling during the early stages of larva development [18]. The final form (position and width) of the wing veins is refined by several subsequent processes. Notch signaling has been shown to specifically control the sharpening of the boundary between pro-vein (the region competent to produce vein fates) and intervein regions in the wing disc [1], [2]. In this system, the Delta production rate is controlled by a gradient of veinless expression diminishing outward from the center of the pro-vein region (Fig. 2A, left). Notch signaling is observed in two sharply defined side-bands, which restrict further vein development to the region between them (Fig. 2A, right).

Bottom Line: It generally remains unclear, however, how this mutual inactivation and the resulting switching behavior can impact developmental patterning circuits.For lateral inhibition, we find that mutual inactivation speeds up patterning dynamics, relieves the need for cooperative regulatory interactions, and expands the range of parameter values that permit pattern formation, compared to canonical models.Together, these results provide a framework for analysis of more complex Notch-dependent developmental systems.

View Article: PubMed Central - PubMed

Affiliation: Howard Hughes Medical Institute, California Institute of Technology, Pasadena, California, USA.

Show MeSH
Related in: MedlinePlus