Systematic modeling-driven experiments identify distinct molecular clockworks underlying hierarchically organized pacemaker neurons

Significance The hierarchically organized master and slave clock neurons are widely believed to generate circadian rhythms via an identical molecular clockwork. However, their different roles in regulating those rhythms raise the question of whether their molecular clockworks differ. Here, leveraging systematic model-driven in vivo experiments for an unbiased search for their heterogeneity, we found that the master clock neurons have higher synthesis and turnover rates of repressor and lower activator levels than the slave clock neurons. Further in silico analysis revealed that this distinguished molecular clockwork of the master clock neurons allows them to generate strong rhythms but also to flexibly adjust rhythms upon environmental perturbation. This explains how the circadian clock can have two contradictory properties, robustness and flexibility.