Prominent daily physiological and behavioural rhythms are orchestrated by self-sustained biological oscillators called circadian clocks, which have an internally driven 24-hour day-night rhythm and are controlled by a transcriptional autoregulatory feedback loop involving multiple clock genes. 

Clock function arises from the molecular oscillator within each cell and extends anatomically to form an organism-wide system. While the molecular components of circadian clock are well characterized, the mechanisms by which long-term circadian homeostasis and oscillation are achieved throughout complex systems and anatomical regions are poorly understood.

In study published in Nature Communications, a research team led by Prof. MIE Jie and Prof. GUI Jianfang from the Institute of Hydrobiology (IHB) of the Chinese Academy of Sciences, along with Prof. XIAO Rui from Wuhan University, revealed that the endocrine factor anti-Müllerian hormone (Amh) ensures precise gating of the major output pathways of circadian information, thereby maintaining rhythm coherence and circadian homoeostasis at both tissue and systemic levels.

The researchers found that Amh signalling is essential for sustaining robust circadian oscillations of molecular clocks and hormonal and behavioural rhythms. They showed that Amh primarily acts on somatotropes and gonadotropes in the pituitary. Besides, single-cell RNA sequencing revealed the lineage-specific regulation of the pituitary circadian clock by Amh.

To elucidate the molecular mechanisms by which Amh regulates circadian rhythms, the researchers conducted a series of in vivo and in vitro experiments. They confirmed that the Bmpr2a protein serves as the type II receptor for Amh, and knockout of bmpr2a results in the disruption of the circadian clock and behavioural rhythms, mirroring the phenotypes observed in amh mutants.

Furthermore, the researchers revealed that phospho-Smad1/5/9 (P-Smad1/5/9) binds to most clock genes in wild-type pituitary, whereas such binding is significantly reduced in both amh and bmpr2a mutants. They showed that Amh-induced effect on clock gene expression can 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 through multiple evolutionarily conserved clock-controlled elements.

This study reveals a novel molecular mechanism of endocrine-clock crosstalk, offering crucial insights into neuroendocrine regulation of vertebrate circadian rhythms and long-term homeostasis. Besides, it provides a theoretical basis for the genetic improvement of fish economic traits such as growth and stress resistance.