Compensatory Flux Changes within an Endocytic Trafficking Network Maintain Thermal Robustness of Notch Signaling

Summary

Developmental signaling is remarkably robust to environmental variation, including temperature. For example, in ectothermic animals such as Drosophila, Notch signaling is maintained within functional limits across a wide temperature range. We combine experimental and computational approaches to show that temperature compensation of Notch signaling is achieved by an unexpected variety of endocytic-dependent routes to Notch activation which, when superimposed on ligand-induced activation, act as a robustness module. Thermal compensation arises through an altered balance of fluxes within competing trafficking routes, coupled with temperature-dependent ubiquitination of Notch. This flexible ensemble of trafficking routes supports Notch signaling at low temperature but can be switched to restrain Notch signaling at high temperature and thus compensates for the inherent temperature sensitivity of ligand-induced activation. The outcome is to extend the physiological range over which normal development can occur. Similar mechanisms may provide thermal robustness for other developmental signals.

Graphical Abstract

Highlights

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  There are multiple routes to Notch activation, differently affected by temperature

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  Dx and Su(dx) promote clathrin-dependent and -independent Notch endocytosis

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  Notch endocytosis through the distinct routes can up- or downregulate signaling

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  Flux changes within endocytic network ensure Notch signal is robust to temperature

Abstract

The robustness of Notch signaling to temperature changes during fly development is achieved by a network of competing temperature-dependent endocytic trafficking routes. These stabilize signaling levels in the face of temperature variation that influences ligand-induced receptor activation.