title: Threshold responses to morphogen gradients by zero-order ultrasensitivity.
abstract: Translating a graded morphogen distribution into tight response borders is central to all developmental processes. Yet, the molecular mechanisms generating such behavior are poorly understood. During patterning of the Drosophila embryonic ventral ectoderm, a graded mitogen-activated protein kinase (MAPK) activation is converted into an all-or-none degradation switch of the Yan transcriptional repressor. Replacing the cardinal phosphorylated amino acid of Yan by a phosphomimetic residue allowed its degradation in a MAPK-independent manner, consistent with Yan phosphorylation being the critical event in generating the switch. Several alternative threshold mechanisms that could, in principle, be realized by this phosphorylation, including first order, cooperativity, positive feedback and zero-order ultrasensitivity, were analyzed. We found that they can be distinguished by their kinetics and steady-state responses to Yan overexpression. In agreement with the predictions for zero-order kinetics, an increase in Yan levels did not shift the degradation border, but significantly elevated the time required to reach steady state. We propose that a reversible loop of Yan phosphorylation implements a zero-order ultrasensitivity-like threshold mechanism, with the capacity to form sharp thresholds that are independent of the level of Yan.
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Gustavo J
authors.initials: GJ
authors.lastname: Melen
authors.forename: Sagi
authors.initials: S
authors.lastname: Levy
authors.forename: Naama
authors.initials: N
authors.lastname: Barkai
authors.forename: Ben-Zion
authors.initials: BZ
authors.lastname: Shilo
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D019521:Body Patterning / Q000235:genetics / Q000502:physiology*; D019295:Computational Biology; D029721:Drosophila Proteins / Q000235:genetics / Q000502:physiology*; D004331:Drosophila melanogaster / Q000196:embryology* / Q000235:genetics; D004475:Ectoderm / Q000502:physiology / Q000648:ultrastructure; D004625:Embryo, Nonmammalian / Q000502:physiology / Q000648:ultrastructure; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000502:physiology; D066246:ErbB Receptors / Q000502:physiology; D005136:Eye Proteins / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D007700:Kinetics; D020935:MAP Kinase Signaling System; D008433:Mathematics; D008565:Membrane Proteins / Q000502:physiology; D008954:Models, Biological; D009024:Morphogenesis / Q000235:genetics / Q000502:physiology; D010447:Peptide Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D012097:Repressor Proteins / Q000502:physiology*
chemical_list: C076188:AOP protein, Drosophila; D029721:Drosophila Proteins; D005136:Eye Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D012097:Repressor Proteins; C428945:edl protein, Drosophila; C076026:spi protein, Drosophila; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D010447:Peptide Hydrolases