Anti-Müllerian hormone signalling sustains circadian homeostasis in zebrafish

Circadian clocks temporally orchestrate the behavioural and physiological rhythms. The core molecules establishing the circadian clock are clear; however, the critical signalling pathways that cause or favour the homeostasis are poorly understood. Here, we report that anti-Müllerian hormone (Amh)-mediated signalling plays an important role in sustaining circadian homeostasis in zebrafish. Remarkably, amh knockout dampens molecular clock oscillations and disrupts both behavioural and hormonal circadian rhythms, which were recapitulated in bmpr2a null mutants. Somatotropes and gonadotropes were identified as Amh-positive pituitary cell populations. Single-cell transcriptome analysis further revealed a lineage-specific regulation of pituitary clock by Amh. Moreover, Amh-induced effect on clock gene expression could be abolished by blocking Smad1/5/9 phosphorylation and bmpr2a knockout. Mechanistically, Amh binds to its receptors, Bmpr2a/Bmpr1bb, which in turn activate Smad1/5/9 by phosphorylation and promote circadian gene expression. Our findings reveal a key hormone signalling pathway for circadian homeostasis in zebrafish with implications for rhythmic organ functions and circadian health. Overall design: Molecular components of the circadian clock are known; however, the mechanisms by which long-term circadian homeostasis and oscillation are achieved throughout complex systems and anatomical regions are poorly understood. We performed CUT&Tag and single-cell RNA sequencing of wildtype, amh or bmpr2a knockout zebrafish pituitary to investigate the molecular mechanism by which Amh signaling sustains circadian homeostasis.