A repressor-decay timer for robust temporal patterning in embryonic Drosophila neuroblast lineages

Biological timers synchronize patterning processes during embryonic development. In the Drosophila embryo, neural progenitors (neuroblasts; NBs) produce a sequence of unique neurons whose identities depend on the sequential expression of temporal transcription factors (TTFs). The stereotypy and precision of the NB lineages indicate reproducible temporal progression of the TTF timer. To examine the basis of this robustness, we combine theory and experiments. The TTF timer is commonly described as a relay of activators, but its regulatory circuit is also consistent with a repressor-decay timer, in which expression of each TTF begins once its repressor is sufficiently reduced. We find that repressor-decay timers are more robust to parameter variations compared to activator-relay timers. This suggests that the in-vivo TTF sequence progresses primarily by repressor-decay, a prediction that we support experimentally. Our results emphasize the role of robustness in the evolutionary design of patterning circuits.