title: Canalization of gene expression in the Drosophila blastoderm by gap gene cross regulation.
abstract: Developing embryos exhibit a robust capability to reduce phenotypic variations that occur naturally or as a result of experimental manipulation. This reduction in variation occurs by an epigenetic mechanism called canalization, a phenomenon which has resisted understanding because of a lack of necessary molecular data and of appropriate gene regulation models. In recent years, quantitative gene expression data have become available for the segment determination process in the Drosophila blastoderm, revealing a specific instance of canalization. These data show that the variation of the zygotic segmentation gene expression patterns is markedly reduced compared to earlier levels by the time gastrulation begins, and this variation is significantly lower than the variation of the maternal protein gradient Bicoid. We used a predictive dynamical model of gene regulation to study the effect of Bicoid variation on the downstream gap genes. The model correctly predicts the reduced variation of the gap gene expression patterns and allows the characterization of the canalizing mechanism. We show that the canalization is the result of specific regulatory interactions among the zygotic gap genes. We demonstrate the validity of this explanation by showing that variation is increased in embryos mutant for two gap genes, Krüppel and knirps, disproving competing proposals that canalization is due to an undiscovered morphogen, or that it does not take place at all. In an accompanying article in PLoS Computational Biology (doi:10.1371/journal.pcbi.1000303), we show that cross regulation between the gap genes causes their expression to approach dynamical attractors, reducing initial variation and providing a robust output. These results demonstrate that the Bicoid gradient is not sufficient to produce gap gene borders having the low variance observed, and instead this low variance is generated by gap gene cross regulation. More generally, we show that the complex multigenic phenomenon of canalization can be understood at a quantitative and predictive level by the application of a precise dynamical model.
authors.affiliation: Department of Applied Mathematics and Statistics, and Center for Developmental Genetics, Stony Brook University, Stony Brook, New York, United States of America.
authors.lastname: Manu
authors.forename: Svetlana
authors.initials: S
authors.lastname: Surkova
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Spirov
authors.forename: Vitaly V
authors.initials: VV
authors.lastname: Gursky
authors.forename: Hilde
authors.initials: H
authors.lastname: Janssens
authors.forename: Ah-Ram
authors.initials: AR
authors.lastname: Kim
authors.forename: Ovidiu
authors.initials: O
authors.lastname: Radulescu
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Vanario-Alonso
authors.forename: David H
authors.initials: DH
authors.lastname: Sharp
authors.forename: Maria
authors.initials: M
authors.lastname: Samsonova
authors.forename: John
authors.initials: J
authors.lastname: Reinitz
mesh_terms: D000818:Animals; D001756:Blastoderm / Q000196:embryology / Q000378:metabolism*; D019521:Body Patterning / Q000235:genetics; D029721:Drosophila Proteins / Q000172:deficiency / Q000235:genetics; D004331:Drosophila melanogaster / Q000196:embryology / Q000235:genetics*; D004777:Environment; D044127:Epigenesis, Genetic; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D014644:Genetic Variation; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000172:deficiency / Q000235:genetics; D008962:Models, Theoretical; D012097:Repressor Proteins / Q000172:deficiency / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D020690:GTPase-Activating Proteins; D018398:Homeodomain Proteins; C497244:Kr protein, Drosophila; D051741:Kruppel-Like Transcription Factors; D012097:Repressor Proteins; D015534:Trans-Activators; C056478:bcd protein, Drosophila; C074089:kni protein, Drosophila