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      Core clock gene Bmal1 deprivation impairs steroidogenesis in mice luteinized follicle cells

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          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.

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          We show that, in the mouse, the core mechanism for the master circadian clock consists of interacting positive and negative transcription and translation feedback loops. Analysis of Clock/Clock mutant mice, homozygous Period2(Brdm1) mutants, and Cryptochrome-deficient mice reveals substantially altered Bmal1 rhythms, consistent with a dominant role of PERIOD2 in the positive regulation of the Bmal1 loop. In vitro analysis of CRYPTOCHROME inhibition of CLOCK: BMAL1-mediated transcription shows that the inhibition is through direct protein:protein interactions, independent of the PERIOD and TIMELESS proteins. PERIOD2 is a positive regulator of the Bmal1 loop, and CRYPTOCHROMES are the negative regulators of the Period and Cryptochrome cycles.
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                Author and article information

                Reproduction (Cambridge, England)
                Bioscientifica Ltd (Bristol )
                December 2020
                17 September 2020
                : 160
                : 6
                : 955-967
                [1 ]Reproductive Medicine Center, The First Affiliated Hospital of Sun Yat-sen University , Guangdong, Guangzhou, China
                [2 ]Reproductive Medicine Center , Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
                [3 ]Guangdong Provincial Key Laboratory of Reproductive Medicine , First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
                Author notes
                Correspondence should be addressed to Y Xu; Email: xuyanwen663000@ 123456126.com
                © 2020 The authors

                This work is licensed under a Creative Commons Attribution 4.0 International License.


                Obstetrics & Gynecology


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