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

Glucocorticoids (GCs) have been proposed as maternal-fetal communication signals. However, fetal circadian rhythms are initially shielded from maternal entrainment, in addition to delayed circadian clock emergence due to CLOCK suppression. Premature CLOCK/BMAL1 activation disrupts Hes7-driven somite-like structure in gastruloids. Given the genomic proximity of Per1 to Hes7 and their transcriptional ripple effect, the physiological significance of delayed cell-autonomous circadian clock development and the temporal program of maternal-fetal communication during the developmental process have remained unclear. Here, based on a marked decline in Hsd11b2, encoding a GC-inactivating 11{beta}-HSD2 enzyme, during organogenesis, we performed split-litter embryo-transfer experiments in which Hsd11b2 knockout (KO) and wild-type (WT) embryos shared the same maternal environment. 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 11{beta}-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. Significance StatementGCs have been proposed as maternal-fetal communication signals. However, initially, circadian clock is not only suppressed but also shielded from maternal entrainment. Premature CLOCK/BMAL1 activation can disrupt Hes7-driven somitogenesis. In a split-litter Hsd11b2-knockout model, AF GCs remained low and arrhythmic basally but surged after maternal stress in KO embryos, inducing Per1. Despite a genomic position effect of Per1-Hes7 and their putative transcriptional coupling, stress-associated or pharmacological GC exposure did not cause segmentation defects in vivo or disrupt Hes7 oscillations in vitro, whereas CLOCK/BMAL1-driven arrest of Hes7 oscillations persisted in gastruloids despite ectopic Hes7 rescue. These findings identify 11{beta}-HSD2 as a developmental buffer and support the physiological importance of the temporal architecture controlling the timing of circadian clock development.