11β‑HSD2 buffers fetal glucocorticoid exposure inducing Per1 expression under maternal stress

Amniotic fluid (AF) GCs remained low and arrhythmic under basal conditions. In contrast, maternal stress caused a pronounced GC surge and Per1 induction in KO, suggesting that 11β-HSD2 buffers acute maternal GC surges. Despite the genomic proximity of Per1 to Hes7 and their transcriptional ripple effect, stress-associated and pharmacological GC exposure recapitulated no overt segmentation defects in vivo.

Embryonic stem cell-derived gastruloid assays confirmed that neither GC exposure nor Per1 induction arrested Hes7 oscillations, whereas premature CLOCK/BMAL1 activation impaired these processes even in Hes7 KO gastruloid with ectopic rescue, suggesting that interference with the segmentation clock is mediated by premature CLOCK/BMAL1 activation, not by GC-induced Per1 expression. These findings clearly show that maternal GC signals are selectively buffered during early development.

In addition, suppression of CLOCK/BMAL1 activity preserves segmentation clock function, indicating delayed circadian clock emergence is actively regulated during embryogenesis.