title: Mathematical modeling elucidates the role of transcriptional feedback in gibberellin signaling.
abstract: The hormone gibberellin (GA) is a key regulator of plant growth. Many of the components of the gibberellin signal transduction [e.g., GIBBERELLIN INSENSITIVE DWARF 1 (GID1) and DELLA], biosynthesis [e.g., GA 20-oxidase (GA20ox) and GA3ox], and deactivation pathways have been identified. Gibberellin binds its receptor, GID1, to form a complex that mediates the degradation of DELLA proteins. In this way, gibberellin relieves DELLA-dependent growth repression. However, gibberellin regulates expression of GID1, GA20ox, and GA3ox, and there is also evidence that it regulates DELLA expression. In this paper, we use integrated mathematical modeling and experiments to understand how these feedback loops interact to control gibberellin signaling. Model simulations are in good agreement with in vitro data on the signal transduction and biosynthesis pathways and in vivo data on the expression levels of gibberellin-responsive genes. We find that GA-GID1 interactions are characterized by two timescales (because of a lid on GID1 that can open and close slowly relative to GA-GID1 binding and dissociation). Furthermore, the model accurately predicts the response to exogenous gibberellin after a number of chemical and genetic perturbations. Finally, we investigate the role of the various feedback loops in gibberellin signaling. We find that regulation of GA20ox transcription plays a significant role in both modulating the level of endogenous gibberellin and generating overshoots after the removal of exogenous gibberellin. Moreover, although the contribution of other individual feedback loops seems relatively small, GID1 and DELLA transcriptional regulation acts synergistically with GA20ox feedback.
authors.affiliation: Centre for Plant Integrative Biology, School of Biosciences,  University of Nottingham, Loughborough LE12 5RD,  United Kingdom.
authors.forename: Alistair M
authors.initials: AM
authors.lastname: Middleton
authors.forename: Susana
authors.initials: S
authors.lastname: Úbeda-Tomás
authors.forename: Jayne
authors.initials: J
authors.lastname: Griffiths
authors.forename: Tara
authors.initials: T
authors.lastname: Holman
authors.forename: Peter
authors.initials: P
authors.lastname: Hedden
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Thomas
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Phillips
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Holdsworth
authors.forename: Malcolm J
authors.initials: MJ
authors.lastname: Bennett
authors.forename: John R
authors.initials: JR
authors.lastname: King
authors.forename: Markus R
authors.initials: MR
authors.lastname: Owen
mesh_terms: D000465:Algorithms; D017360:Arabidopsis / Q000235:genetics / Q000378:metabolism; D029681:Arabidopsis Proteins / Q000235:genetics / Q000378:metabolism; D025461:Feedback, Physiological / Q000187:drug effects; D018506:Gene Expression Regulation, Plant / Q000187:drug effects; D005875:Gibberellins / Q000378:metabolism* / Q000494:pharmacology; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism; D008957:Models, Genetic; D010937:Plant Growth Regulators / Q000378:metabolism / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics*
chemical_list: D029681:Arabidopsis Proteins; C109555:GAI protein, Arabidopsis; C512225:GID1a protein, Arabidopsis; D005875:Gibberellins; D010937:Plant Growth Regulators; D011956:Receptors, Cell Surface; D006899:Mixed Function Oxygenases; C089210:gibberellin, 2-oxoglutarate-oxygen oxidoreductase (20-hydroxylating, oxidizing); C108186:gibberellin 3beta-hydroxylase