title: A WntD-Dependent Integral Feedback Loop Attenuates Variability in Drosophila Toll Signaling.
abstract: Patterning by morphogen gradients relies on the capacity to generate reproducible distribution profiles. Morphogen spread depends on kinetic parameters, including diffusion and degradation rates, which vary between embryos, raising the question of how variability is controlled. We examined this in the context of Toll-dependent dorsoventral (DV) patterning of the Drosophila embryo. We find that low embryo-to-embryo variability in DV patterning relies on wntD, a Toll-target gene expressed initially at the posterior pole. WntD protein is secreted and disperses in the extracellular milieu, associates with its receptor Frizzled4, and inhibits the Toll pathway by blocking the Toll extracellular domain. Mathematical modeling predicts that WntD accumulates until the Toll gradient narrows to its desired spread, and we support this feedback experimentally. This circuit exemplifies a broadly applicable induction-contraction mechanism, which reduces patterning variability through a restricted morphogen-dependent expression of a secreted diffusible inhibitor.
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Neta
authors.initials: N
authors.lastname: Rahimi
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Inna
authors.initials: I
authors.lastname: Averbukh
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Haskel-Ittah
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Neta
authors.initials: N
authors.lastname: Degani
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Eyal D
authors.initials: ED
authors.lastname: Schejter
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address: naama.barkai@weizmann.ac.il.
authors.forename: Naama
authors.initials: N
authors.lastname: Barkai
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address: benny.shilo@weizmann.ac.il.
authors.forename: Ben-Zion
authors.initials: BZ
authors.lastname: Shilo
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000235:genetics / Q000502:physiology*; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism*; D004625:Embryo, Nonmammalian / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051193:Toll-Like Receptors / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C068721:Tl protein, Drosophila; D051193:Toll-Like Receptors; D014157:Transcription Factors; C504611:WntD protein, Drosophila