Notch mediated lateral inhibition is shaped by morphological differences to reinforce bias toward signal-sending or receiving roles

Summary During neurogenesis, neuroblasts are selected from proneural-competent cells through lateral inhibition, a process controlled by the evolutionarily conserved Notch signalling pathway. By tracking transcription from Notch-target genes and cell morphologies in real time, we discovered that the presumptive neuroblast never initiates target-gene transcription. This implies a pre-existing bias directs Notch signalling. The bias correlates with a heterogeneity in apical cell areas which is further reinforced during neuroblast selection. Additionally, the length and duration of neuroblast-neighbour cell contacts predict the likelihood of transcription. Using mathematical modelling we show that lateral inhibition seeded with subtle morphological differences can bias cells toward signal-sending or receiving roles before transcriptional feedback occurs. Notch activation further alters apical cell area, reinforcing the initial bias. We propose that signalling and cell mechanics work together to ensure the robust selection of a single neural precursor.