d-Asb11 is an essential mediator of canonical Delta-Notch signalling.
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.
Diks
Sander H
SH
Deptartment of Cell Biology, University Medical Center Groningen, University of Groningen, A. Deusinglaan 1, NL-9713 AV Groningen, The Netherlands.
Sartori da Silva
Maria A
MA
Hillebrands
Jan-Luuk
JL
Bink
Robert J
RJ
Versteeg
Henri H
HH
van Rooijen
Carina
C
Brouwers
Anke
A
Chitnis
Ajay B
AB
Peppelenbosch
Maikel P
MP
Zivkovic
Danica
D
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*
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