title: Cullin-3 regulates pattern formation, external sensory organ development and cell survival during Drosophila development.
abstract: Ubiquitin-mediated proteolysis regulates the steady-state abundance of proteins and controls cellular homoeostasis by abrupt elimination of key effector proteins. A multienzyme system targets proteins for destruction through the covalent attachment of a multiubiquitin chain. The specificity and timing of protein ubiquitination is controlled by ubiquitin ligases, such as the Skp1-Cullin-F box protein complex. Cullins are major components of SCF complexes, and have been implicated in degradation of key regulatory molecules including Cyclin E, beta-catenin and Cubitus interruptus. Here, we describe the genetic identification and molecular characterisation of the Drosophila Cullin-3 homologue. Perturbation of Cullin-3 function has pleiotropic effects during development, including defects in external sensory organ development, pattern formation and cell growth and survival. Loss or overexpression of Cullin-3 causes an increase or decrease, respectively, in external sensory organ formation, implicating Cullin-3 function in regulating the commitment of cells to the neural fate. We also find that Cullin-3 function modulates Hedgehog signalling by regulating the stability of full-length Cubitus interruptus (Ci155). Loss of Cullin-3 function in eye discs but not other imaginal discs promotes cell-autonomous accumulation of Ci155. Conversely, overexpression of Cullin-3 results in a cell-autonomous stabilisation of Ci155 in wing, haltere and leg, but not eye, imaginal discs suggesting tissue-specific regulation of Cullin-3 function. The diverse nature of Cullin-3 phenotypes highlights the importance of targeted proteolysis during Drosophila development.
authors.affiliation: Department of Genetics, Washington University School of Medicine, 4566 Scott Avenue Box 8232, St Louis, MO 63110, USA.
authors.forename: Hemlata
authors.initials: H
authors.lastname: Mistry
authors.forename: Beth A
authors.initials: BA
authors.lastname: Wilson
authors.forename: Ian J H
authors.initials: IJ
authors.lastname: Roberts
authors.forename: Cahir J
authors.initials: CJ
authors.lastname: O'Kane
authors.forename: James B
authors.initials: JB
authors.lastname: Skeath
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019521:Body Patterning / Q000235:genetics / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D004330:Drosophila / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins; D008969:Molecular Sequence Data; D012679:Sense Organs / Q000196:embryology* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D014921:Wings, Animal / Q000002:abnormalities
chemical_list: D018797:Cell Cycle Proteins; C503647:Cul3 protein, Drosophila; D044842:Cullin Proteins; D029721:Drosophila Proteins; D044767:Ubiquitin-Protein Ligases