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

During neurogenesis, neuroblasts (NBs) are selected from proneural-competent cells through lateral inhibition, a process controlled by the evolutionarily conserved Notch signaling pathway. By tracking transcription from Notch-target genes and cell morphologies in real time, we discovered that the presumptive NB never initiates target-gene transcription. This implies that a pre-existing bias directs Notch signaling. The bias correlates with a heterogeneity in apical cell areas that is further reinforced during NB selection. Additionally, the length and duration of NB-neighbor cell contacts predict the likelihood of transcription. Using mathematical modeling, 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 signaling and cell mechanics work together to ensure the robust selection of a single neural precursor.