Cis-inhibition suppresses basal Notch signalling during sensory organ precursor selection

The emergence of the sensory organ precursor (SOP) from the proneural equivalence group in Drosophila melanogaster is a paradigm for studying single cell fate specification through the process of lateral inhibition. Classical lateral inhibition models describing this selection process are based on a transcriptional feedback mechanism where inhibitory signals between neighbouring cells, mediated by Notch pathway, are coupled to an intracellular circuit regulating the expression of the Notch ligand Delta (Dl). It was previously shown that in addition to its ability to trans-activate Notch in neighbouring cells, Dl can also cis-inhibit Notch in the same cell. However, it remains unclear what role does cis-inhibition play during SOP selection, and how it contributes to the selection of only one SOP. Here we address these questions using the unexpected observation that the mammalian ligand Delta-like 1 (Dll1) can trans-activate but not cis-inhibit Notch in Drosophila. We develop a mathematical model for SOP selection, termed the two-channel SOP (TCS) model, where Dl activity, but not its expression, is regulated by two channels associated with the two E3 ubiquitin ligases Neuralized (Neur) and Mindbomb1 (Mib1). While the Neur-dependent channel is regulated by Notch signalling, the Mib1-dependent channel is not, leading to tissue-wide basal inhibitory activity. We show theoretically and experimentally that cis-inhibition is required for suppressing Mib1-dependent basal Notch activity. Thus, our results highlight the trade-off between basal Notch activity and cis-inhibition as a mechanism for singling out an SOP from the proneural equivalence group.