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Abstract
Luteinization is the event of corpus luteum formation, a way of follicle cells transformation and a process of steroidogenesis alteration. As the core clock gene, Bmal1 was involved in the regulation of ovulation process and luteal function afterwards. Till now, the underlying roles of luteinization played by Bmal1 remain unknown. To explore the unique role of Bmal1 in luteal steroidogenesis and its underlying pathway, we investigated the luteal hormone synthesis profile in Bmal1 knockout female mice. We found that luteal hormone synthesis was notably impaired, and phosphorylation of PI3K/NfκB pathway was significantly activated. Then, the results were verified in in vitro cultured cells, including isolated Bmal1 interference granulosa cells (GCs) and theca cells (TCs), respectively. Hormones levels of supernatant culture media and mRNA expressions of steroidogenesis-associated genes (star, Hsd3β2, cyp19a1 in GCs, Lhcgr, star, Hsd3β2, cyp17a1 in TCs) were mutually decreased, while the phosphorylation of PI3K/NfκB was promoted during in vitro luteinization. After PI3K specific-inhibitor LY294002 intervention, mRNA expressions of Lhcgr and Hsd3β2 were partially rescued in Bmal1 interference TCs, together with significantly increased androstenedione and T synthesis. Further exploration in TCs demonstrated BMAL1 interacted directly but negatively with NfκB p65 (RelA), a subunit which was supposed as a mediator in Bmal1-governed PI3K signaling regulation. Taken together, we verified the novel role of Bmal1 in luteal steroidogenesis, achieving by negative interplay with RelA-mediated PI3K/NfκB pathway.
Highlights
Brain and muscle Arnt-like 1 (Bmal1) is the core component of the internal circadian clock system, which has been proved to be indispensable to maintain the mammalian circadian rhythms (Huang et al 2012, Sellix 2015)
Thereafter, serum E2 rose in advance in Bmal1−/− ones, reaching to 28.4 ± 4.4 pg/mL at 96 h, while the E2 remained at a lower level of 17.2 ± 5.7 pg/mL in WT (P = 0.03)
The present study showed that deprivation of Bmal1, as a molecular-switch of the circadian oscillation, altered luteal phase profile in Bmal1 null mice
Summary
Brain and muscle Arnt-like 1 (Bmal1) is the core component of the internal circadian clock system, which has been proved to be indispensable to maintain the mammalian circadian rhythms (Huang et al 2012, Sellix 2015). Bmal deprivation could bring about endogenous or entrainable oscillation alteration (Boden et al 2010). Up to 10% of transcriptome in human was expressed in circadian manner (Panda et al 2002). Extensive noncircadian regulation patterns of Bmal were confirmed in many peripheral biological processes (Alvarez et al 2003). Germline Bmal loss results in an acceleration of aging but adult-life inducible knockout ones do not have such gross effects, while both are deficient in the circadian cock (Yang et al 2016)
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