The circadian clock orchestrates spermatogonial differentiation and fertilization by regulating retinoic acid (RA) signaling in vertebrates

Abstract

Abstract The circadian clock generates and maintains ∼24-hour oscillations in almost all organs. The testis, however, remains mysterious without a clear understanding of its circadian functions. Our time-series transcriptome analysis reveals more than 1,000 rhythmically expressed genes in the zebrafish and mouse testes, respectively. Canonical circadian clock genes are rhythmically expressed in Sertoli cells and regulate retinoic acid (RA) production, which is also evidenced by their co-expression with RA synthesis genes in single Sertoli cells. Genetic and pharmacological manipulations and temporal desynchronization revealed that the circadian clock-regulated RA signaling synchronizes spermatogonial differentiation via zbtb16a and promotes fertilization via izumo1 in zebrafish. Our findings indicate that the testicular circadian clock contributes to reproduction in a cell-specific manner through RA signaling, highlighting circadian roles in male fertility.