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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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Simplified lateral inhibition with mutual inactivation (SLIMI).(A) Schematic of a simplified lateral inhibition circuit architecture. Here, Notch signaling activates expression of the Notch gene. Notch activation thus leads to higher Notch levels which, in turn, lead to lower levels of free DSL due to the mutual inactivation interaction between Notch and DSL proteins in cis (dashed arrows). (B) Calculation of the MLE for the SLIMI model. The SLIMI model can support patterning without cooperative feedback over a large region of parameter space. Color scale is the same as in Fig. 5A–D. Equations and parameters are described in the Supporting Information Text S1.3 and Table S1, respectively.
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pcbi-1002069-g006: Simplified lateral inhibition with mutual inactivation (SLIMI).(A) Schematic of a simplified lateral inhibition circuit architecture. Here, Notch signaling activates expression of the Notch gene. Notch activation thus leads to higher Notch levels which, in turn, lead to lower levels of free DSL due to the mutual inactivation interaction between Notch and DSL proteins in cis (dashed arrows). (B) Calculation of the MLE for the SLIMI model. The SLIMI model can support patterning without cooperative feedback over a large region of parameter space. Color scale is the same as in Fig. 5A–D. Equations and parameters are described in the Supporting Information Text S1.3 and Table S1, respectively.

Mentions: Mutual inactivation can have a more dramatic effect on patterning: Besides improving the performance of standard patterning circuits, it can enable an altogether different, and simpler, lateral inhibition circuit architecture. The essential requirement for lateral inhibition is that increased Notch activity in one cell reduces its ability to signal to its neighbors. In the presence of mutual inactivation, one way to achieve this is for Notch activity to directly up-regulate Notch expression (Fig. 6A). Increased levels of Notch result in more rapid removal of DSL through the mutual inactivation interaction, effectively down-regulating it. Thus, a circuit in which Notch activates its own expression implements lateral inhibition with only a single level of transcriptional feedback, i.e. instead of Notch activating a repressor of DSL, there is direct downregulation of DSL through the mutual inactivation interaction. This type of autoregulation has been observed in some cases, such as the C. elegans AC/VU fate determination system [27]. We term this circuit architecture ‘Simplest Lateral Inhibition with Mutual Inactivation’ (SLIMI). Linear stability analysis of this SLIMI circuit (Fig. 6B) shows that patterning can occur across a broad range of parameter values. Moreover, as with the LIMI model, SLIMI does not require explicit cooperativity for patterning. Thus, lateral inhibition can be achieved with a startlingly simple circuit architecture.


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)

Simplified lateral inhibition with mutual inactivation (SLIMI).(A) Schematic of a simplified lateral inhibition circuit architecture. Here, Notch signaling activates expression of the Notch gene. Notch activation thus leads to higher Notch levels which, in turn, lead to lower levels of free DSL due to the mutual inactivation interaction between Notch and DSL proteins in cis (dashed arrows). (B) Calculation of the MLE for the SLIMI model. The SLIMI model can support patterning without cooperative feedback over a large region of parameter space. Color scale is the same as in Fig. 5A–D. Equations and parameters are described in the Supporting Information Text S1.3 and Table S1, respectively.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3111533&req=5

pcbi-1002069-g006: Simplified lateral inhibition with mutual inactivation (SLIMI).(A) Schematic of a simplified lateral inhibition circuit architecture. Here, Notch signaling activates expression of the Notch gene. Notch activation thus leads to higher Notch levels which, in turn, lead to lower levels of free DSL due to the mutual inactivation interaction between Notch and DSL proteins in cis (dashed arrows). (B) Calculation of the MLE for the SLIMI model. The SLIMI model can support patterning without cooperative feedback over a large region of parameter space. Color scale is the same as in Fig. 5A–D. Equations and parameters are described in the Supporting Information Text S1.3 and Table S1, respectively.
Mentions: Mutual inactivation can have a more dramatic effect on patterning: Besides improving the performance of standard patterning circuits, it can enable an altogether different, and simpler, lateral inhibition circuit architecture. The essential requirement for lateral inhibition is that increased Notch activity in one cell reduces its ability to signal to its neighbors. In the presence of mutual inactivation, one way to achieve this is for Notch activity to directly up-regulate Notch expression (Fig. 6A). Increased levels of Notch result in more rapid removal of DSL through the mutual inactivation interaction, effectively down-regulating it. Thus, a circuit in which Notch activates its own expression implements lateral inhibition with only a single level of transcriptional feedback, i.e. instead of Notch activating a repressor of DSL, there is direct downregulation of DSL through the mutual inactivation interaction. This type of autoregulation has been observed in some cases, such as the C. elegans AC/VU fate determination system [27]. We term this circuit architecture ‘Simplest Lateral Inhibition with Mutual Inactivation’ (SLIMI). Linear stability analysis of this SLIMI circuit (Fig. 6B) shows that patterning can occur across a broad range of parameter values. Moreover, as with the LIMI model, SLIMI does not require explicit cooperativity for patterning. Thus, lateral inhibition can be achieved with a startlingly simple circuit architecture.

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