Choroid Plexus Hosts the Earliest Detectable Circadian Clock in the Brain
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Embryonic circadian rhythms support normal development, and maternal chronodisruption is linked to miscarriages and neurodevelopmental risks, yet the identity of the earliest brain circadian oscillator and the mechanisms governing its emergence remain unknown. Using bioluminescent reporters for Per2 and Bmal1 , we identified the developmental window in which autonomous ∼24 h oscillations first appear ex vivo . Contrary to the prevailing view that places the suprachiasmatic nucleus (SCN) as the earliest circadian structure at E14.5–E15.5, we found that the fourth ventricle choroid plexus (4VCP) exhibits PER2::LUC oscillations by E11.5–E12.5. Transcriptional profiling revealed significant phase shifts in multiple clock genes between E11.5 and E13.5, indicating a transition away from maternal synchrony and the onset of a differentiation program. Detailed characterization of these early oscillations showed hallmarks consistent with a saddle-node on an invariant circle (SNIC) bifurcation. Our findings identify the 4VCP as the earliest detectable brain circadian oscillator and clarify the process leading to the onset of the embryonic circadian clock in the brain. These results provide insights into maternal and fetal clock interactions during development, with implications for neonatal care.
Graphical Abstract
Timeline of 4VCP clock emergence before the SCN.
In the embryonic 4VCP, PER2::LUC oscillations appear at E11.5–E12.5, and cellular synchrony increases abruptly around E14.5. Bmal1-ELuc oscillations appear at E13.5. The 4VCP entrains to a 0.5 °C temperature cycle through E16 but not at E18. The lower pie charts and gradients summarize the fraction of embryonic clock genes that are circadian and their correlation with maternal Bmal1 , Dbp , and Per2 expression.
