Critical Roles of the Circadian Transcription Factor BMAL1 in Reproductive Endocrinology and Fertility

Yin Jiang,Junjie Ying,Jinhui Li,Yi Qu,Wenming Xu,Shiping Li,Yan Yue,Tiechao Ruan,Xiaohui Jiang,Ruixi Zhou,Dezhi Mu,Ayuan Zhang

doi:10.3389/fendo.2022.818272

Abstract

Brain and muscle aryl-hydrocarbon receptor nuclear translocator like protein1 (BMAL1), a core component of circadian oscillation, is involved in many physiological activities. Increasing evidence has demonstrated the essential role of BMAL1 in reproductive physiology. For instance, BMAL1-knockout (KO) mice were infertile, with impaired reproductive organs and gametes. Additionally, in BMAL1-KO mice, hormone secretion and signaling of hypothalamus-pituitary-gonadal (H-P-G) hormones were also disrupted, indicating that H-P-G axis was impaired in BMAL1-KO mice. Moreover, both BMAL1-KO mice and BMAL1-knockdown by small interfering RNA (siRNA) in vitro cultured steroidogenic cells showed that BMAL1 was associated with gonadal steroidogenesis and expression of related genes. Importantly, BMAL1 also participates in pathogenesis of human reproductive diseases. In this review, we elaborate on the impaired reproduction of BMAL1-KO mice including the reproductive organs, reproductive endocrine hormones, and reproductive processes, highlighting the vital role of BMAL1 in fertility and reproductive endocrinology.

Highlights

Circadian rhythms play essential roles in various physiological processes as well as the development of organisms, which are known to be largely controlled by a group of transcription factor genes
There, gonadotropin-releasing hormones (GnRH) is consistently recognized as the master regulator for the secretion of downstream gonadotropin, including follicle-stimulating hormone (FSH) and luteinizing hormone (LH) derived from the pituitary [46–51]
As current review has indicated, BMAL1 knockout leads to impaired structures and functions of reproductive organs and gametes, signaling from the hypothalamus to pituitary impaired gonadal hormone secretion and impaired hormone secretion

Summary

INTRODUCTION

Circadian rhythms play essential roles in various physiological processes as well as the development of organisms, which are known to be largely controlled by a group of transcription factor genes. The delayed puberty and the disordered estrous cycle might be attributed to the disrupted production of hormone signals [15] Such abnormal hypothalamus and pituitary hormone secretion and signaling in female BMAL1-KO mice might be associated with the impaired fertility. The abnormal hypothalamus and pituitary hormone secretion and signaling of male BMAL1-KO mice were possibly associated with low sperm counts and impaired mating behaviors in these mice. In the in vitro cell culture of porcine granulosa cells and the TM3 Leydig cell line, the PI3K/AKT/mTOR pathway was suppressed after intervention of BMAL1,with reduced steroidogenesis and increased apoptosis of steroidogenic cells [41, 77] This pathway was reported to be involved in leptin-lepr signaling in the regulation of steroidogenesis [20]. Another mechanistic study revealed that BMAL1 facilitated the migration and invasion of the extra-villous trophoblast (EVT) via the SP1-DNMT1/DAB2IP pathway, which could be the underlying mechanism through which progesterone treatment prevents spontaneous abortion [27]

CONCLUSIONS AND PROSPECTS

Knockout Mice

Findings

AUTHOR CONTRIBUTIONS