title: Compensatory flux changes within an endocytic trafficking network maintain thermal robustness of Notch signaling.
abstract: 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.
authors.affiliation: University of Manchester, Faculty of Life Sciences, Michael Smith Building, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Shimizu
authors.affiliation: University of Manchester, Faculty of Life Sciences, Michael Smith Building, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Woodcock
authors.affiliation: University of Manchester, Faculty of Life Sciences, Michael Smith Building, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Marian B
authors.initials: MB
authors.lastname: Wilkin
authors.affiliation: University of Manchester, Faculty of Life Sciences, Michael Smith Building, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Barbora
authors.initials: B
authors.lastname: Trubenová
authors.affiliation: School of Mathematics and Statistics, University of Sheffield, Hicks Building, Hounsfield Road, Sheffield S3 7RH, UK.
authors.forename: Nicholas A M
authors.initials: NA
authors.lastname: Monk
authors.affiliation: University of Manchester, Faculty of Life Sciences, Michael Smith Building, Oxford Road, Manchester M13 9PT, UK. Electronic address: mbaron@manchester.ac.uk.
authors.forename: Martin
authors.initials: M
authors.lastname: Baron
mesh_terms: D000818:Animals; D015536:Down-Regulation; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D004705:Endocytosis; D008565:Membrane Proteins / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D013696:Temperature; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: C086679:DX protein, Drosophila; D029721:Drosophila Proteins; D008565:Membrane Proteins; C497759:N protein, Drosophila; D051880:Receptors, Notch; C119838:Su(dx) protein, Drosophila; D044767:Ubiquitin-Protein Ligases