title: Feedback control of gene expression variability in the Caenorhabditis elegans Wnt pathway.
abstract: Variability in gene expression contributes to phenotypic heterogeneity even in isogenic populations. Here, we used the stereotyped, Wnt signaling-dependent development of the Caenorhabditis elegans Q neuroblast to probe endogenous mechanisms that control gene expression variability. We found that the key Hox gene that orients Q neuroblast migration exhibits increased gene expression variability in mutants in which Wnt pathway activity has been perturbed. Distinct features of the gene expression distributions prompted us on a systematic search for regulatory interactions, revealing a network of interlocked positive and negative feedback loops. Interestingly, positive feedback appeared to cooperate with negative feedback to reduce variability while keeping the Hox gene expression at elevated levels. A minimal model correctly predicts the increased gene expression variability across mutants. Our results highlight the influence of gene network architecture on expression variability and implicate feedback regulation as an effective mechanism to ensure developmental robustness.
authors.affiliation: Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Ni
authors.initials: N
authors.lastname: Ji
authors.forename: Teije C
authors.initials: TC
authors.lastname: Middelkoop
authors.forename: Remco A
authors.initials: RA
authors.lastname: Mentink
authors.forename: Marco C
authors.initials: MC
authors.lastname: Betist
authors.forename: Satto
authors.initials: S
authors.lastname: Tonegawa
authors.forename: Dylan
authors.initials: D
authors.lastname: Mooijman
authors.forename: Hendrik C
authors.initials: HC
authors.lastname: Korswagen
authors.forename: Alexander
authors.initials: A
authors.lastname: van Oudenaarden
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000166:cytology / Q000235:genetics* / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics; D002465:Cell Movement; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism; D025461:Feedback, Physiological; D051157:Frizzled Receptors / Q000235:genetics / Q000378:metabolism; D053263:Gene Regulatory Networks; D014644:Genetic Variation; D006023:Glycoproteins / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D051153:Wnt Proteins; D060449:Wnt Signaling Pathway
chemical_list: D029742:Caenorhabditis elegans Proteins; C117259:Egl-20 protein, C elegans; D051157:Frizzled Receptors; D006023:Glycoproteins; D018398:Homeodomain Proteins; C081538:Mab-5 protein, C elegans; D014157:Transcription Factors; D051153:Wnt Proteins