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, S. H., Sartori da Silva, M. A., Hillebrands, J-L., Bink, R. J., Versteeg, H. H., van Rooijen, C., Brouwers, A. M., Chitnis, A. B., Peppelenbosch, M. P., & Zivkovic, D. (2008). d-Asb11 is an essential mediator of canonical Delta-Notch signalling. Nature Cell Biology, 10(10), 1190-1198. https://doi.org/10.1038/ncb1779