title: d-Asb11 is an essential mediator of canonical Delta-Notch signalling.
abstract: In canonical Delta-Notch signalling, expression of Delta activates Notch in neighbouring cells, leading to downregulation of Delta in these cells. This process of lateral inhibition results in selection of either Delta-signalling cells or Notch-signalling cells. Here we show that d-Asb11 is an important mediator of this lateral inhibition. In zebrafish embryos, morpholino oligonucleotide (MO)-mediated knockdown of d-Asb11 caused repression of specific Delta-Notch elements and their transcriptional targets, whereas these were induced when d-Asb11 was misexpressed. d-Asb11 also activated legitimate Notch reporters cell-non-autonomously in vitro and in vivo when co-expressed with a Notch reporter. However, it repressed Notch reporters when expressed in Delta-expressing cells. Consistent with these results, d-Asb11 was able to specifically ubiquitylate and degrade DeltaA both in vitro and in vivo. We conclude that d-Asb11 is a component in the regulation of Delta-Notch signalling, important in fine-tuning the lateral inhibition gradients between DeltaA and Notch through a cell non-autonomous mechanism.
authors.affiliation: Deptartment of Cell Biology, University Medical Center Groningen, University of Groningen, A. Deusinglaan 1, NL-9713 AV Groningen, The Netherlands.
authors.forename: Sander H
authors.initials: SH
authors.lastname: Diks
authors.forename: Maria A
authors.initials: MA
authors.lastname: Sartori da Silva
authors.forename: Jan-Luuk
authors.initials: JL
authors.lastname: Hillebrands
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Bink
authors.forename: Henri H
authors.initials: HH
authors.lastname: Versteeg
authors.forename: Carina
authors.initials: C
authors.lastname: van Rooijen
authors.forename: Anke
authors.initials: A
authors.lastname: Brouwers
authors.forename: Ajay B
authors.initials: AB
authors.lastname: Chitnis
authors.forename: Maikel P
authors.initials: MP
authors.lastname: Peppelenbosch
authors.forename: Danica
authors.initials: D
authors.lastname: Zivkovic
mesh_terms: D000818:Animals; D004625:Embryo, Nonmammalian / Q000378:metabolism; D025461:Feedback, Physiological; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000378:metabolism*; D011485:Protein Binding; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics; D015027:Zebrafish / Q000196:embryology / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000378:metabolism*
chemical_list: C514282:Asb11 protein, zebrafish; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051880:Receptors, Notch; D050826:Suppressor of Cytokine Signaling Proteins; D029961:Zebrafish Proteins; C064045:delta protein; C499041:nrarpa protein, zebrafish