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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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Ultrasensitivity due to mutual inactivation of Notch and DSL.(A) Plot of free DSL (red) and free Notch (blue) as a function of DSL production rate, . A sharp switch (high logarithmic derivative) between sender and receiver states occurs when . (B) Schematic illustration of sending and receiving states, showing that while very little signaling occurs when two neighboring cells are both senders (top) or both receivers (middle), strongly biased signaling can occur for the case of neighboring sender and receiver cells (bottom).
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pcbi-1002069-g001: Ultrasensitivity due to mutual inactivation of Notch and DSL.(A) Plot of free DSL (red) and free Notch (blue) as a function of DSL production rate, . A sharp switch (high logarithmic derivative) between sender and receiver states occurs when . (B) Schematic illustration of sending and receiving states, showing that while very little signaling occurs when two neighboring cells are both senders (top) or both receivers (middle), strongly biased signaling can occur for the case of neighboring sender and receiver cells (bottom).

Mentions: In an individual cell, mutual inactivation of Notch and DSL results in an ultrasensitive switch between ‘sending’ (low Notch/high DSL) and ‘receiving’ (low DSL/high Notch) cellular states (see Fig. 1) [11]. A cell with more total Notch than DSL (i.e. with a higher production rate of Notch than DSL given equal first order degradation rates) has an excess of free Notch but very little free DSL, making it a receiver (Fig. 1A, left). Conversely, a cell with more total DSL than Notch would have an excess of DSL and very little Notch, thus becoming a sender (Fig. 1A, right). In either state, both ligand-mediated inhibition of receptor and receptor-mediated inhibition of ligand contribute to the nonlinearity of the system. For a sufficiently strong cis interaction, the transition between these two states becomes very sharp, or ultrasensitive (Fig. 1A). This switch generates strongly-biased signaling if a sender cell interacts with a receiver cell (Fig. 1B, bottom), but if both interacting cells are in the same signaling state (Fig. 1B, top and middle panels) much less signal is transduced.


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)

Ultrasensitivity due to mutual inactivation of Notch and DSL.(A) Plot of free DSL (red) and free Notch (blue) as a function of DSL production rate, . A sharp switch (high logarithmic derivative) between sender and receiver states occurs when . (B) Schematic illustration of sending and receiving states, showing that while very little signaling occurs when two neighboring cells are both senders (top) or both receivers (middle), strongly biased signaling can occur for the case of neighboring sender and receiver cells (bottom).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3111533&req=5

pcbi-1002069-g001: Ultrasensitivity due to mutual inactivation of Notch and DSL.(A) Plot of free DSL (red) and free Notch (blue) as a function of DSL production rate, . A sharp switch (high logarithmic derivative) between sender and receiver states occurs when . (B) Schematic illustration of sending and receiving states, showing that while very little signaling occurs when two neighboring cells are both senders (top) or both receivers (middle), strongly biased signaling can occur for the case of neighboring sender and receiver cells (bottom).
Mentions: In an individual cell, mutual inactivation of Notch and DSL results in an ultrasensitive switch between ‘sending’ (low Notch/high DSL) and ‘receiving’ (low DSL/high Notch) cellular states (see Fig. 1) [11]. A cell with more total Notch than DSL (i.e. with a higher production rate of Notch than DSL given equal first order degradation rates) has an excess of free Notch but very little free DSL, making it a receiver (Fig. 1A, left). Conversely, a cell with more total DSL than Notch would have an excess of DSL and very little Notch, thus becoming a sender (Fig. 1A, right). In either state, both ligand-mediated inhibition of receptor and receptor-mediated inhibition of ligand contribute to the nonlinearity of the system. For a sufficiently strong cis interaction, the transition between these two states becomes very sharp, or ultrasensitive (Fig. 1A). This switch generates strongly-biased signaling if a sender cell interacts with a receiver cell (Fig. 1B, bottom), but if both interacting cells are in the same signaling state (Fig. 1B, top and middle panels) much less signal is transduced.

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