Cyclic LIN-42/PERIOD precisely times stage-specific cell migration through gene circuit dynamics

Abstract Cyclic signals regulate recurring biological processes, yet their role in one-time events is unclear. We studied the timing of dorsalward turning by C. elegans distal tip cells (DTCs), under the control of cyclic LIN-42, using experiments and mathematical modeling. During an early cycle, DTCs remain inactive through combined positive and biphasic feedback loops involving BLMP-1 and LIN-29 transcription factors, along with activation of the DAF-12 receptor. In the subsequent LIN-42 cycle, the SCF-DRE-1 complex degrades BLMP-1, changing the bifurcation point, allowing the system to turn on through a hysteretic switch and become sensitive to a LIN-42 drop. Finally, the decline of LIN-42 triggers DTC turning, an example of noise-induced switching. The mechanism also explains the robustness of DTC timing under reduced DRE-1 activity, and the heterogeneous phenotype in blmp-1;daf-12 mutant. Our findings highlight how successive cyclic signals coordinate with gene circuit dynamics to precisely control developmental timing.