The circadian clock protein BMAL1 is necessary for fertility and proper testosterone production in mice
The circadian clock protein BMAL1 is necessary for fertility and proper testosterone production in mice
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DOI：
10.1177/0748730407311254
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发表时间：
2008-02-01
影响因子：
3.5
通讯作者：
Sehgal, Amita
中科院分区：
文献类型：
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作者：
Alvarez, J. D.;Hansen, Amanda;Sehgal, Amita
尽管生物钟调节哺乳动物生殖生理这一点已得到充分证实，但这种调节发生的分子机制尚不清楚。作者研究了缺乏Bmal1（Arntl，Mop3，生物钟核心基因之一）的小鼠的生殖能力。他们发现，无论是雄性还是雌性Bmal1基因敲除（KO）小鼠均不育。对两性生殖解剖结构的大体和显微镜检查表明类固醇生成存在缺陷。雄性Bmal1基因敲除小鼠的睾酮水平低，促黄体生成素血清浓度高，这表明睾丸间质细胞存在缺陷。重要的是，间质细胞有节律地表达BMAL1蛋白，这表明这种生物钟蛋白对睾酮产生的外周控制。在Bmal1基因敲除小鼠的睾丸和其他类固醇生成组织中，类固醇生成基因的表达降低。特别是，在Bmal1基因敲除小鼠的睾丸中，调节类固醇生成限速步骤的类固醇生成急性调节蛋白（StAR）基因和蛋白的表达降低。体外实验表明BMAL1可增强StAR转录，这表明BMAL1对间质细胞中StAR表达有直接影响。雄性Bmal1基因敲除小鼠的其他激素缺陷表明，BMAL1在睾丸之外的生殖生理中也具有功能。这些结果增进了对生物钟如何调节生殖的理解。
Although it is well established that the circadian clock regulates mammalian reproductive physiology, the molecular mechanisms by which this regulation occurs are not clear. The authors investigated the reproductive capacity of mice lacking Bmal1 (Arntl, Mop3), one of the central circadian clock genes. They found that both male and female Bmal1 knockout (KO) mice are infertile. Gross and microscopic inspection of the reproductive anatomy of both sexes suggested deficiencies in steroidogenesis. Male Bmal1 KO mice had low testosterone and high luteinizing hormone serum concentrations, suggesting a defect in testicular Leydig cells. Importantly, Leydig cells rhythmically express BMAL1 protein, suggesting peripheral control of testosterone production by this clock protein. Expression of steroidogenic genes was reduced in testes and other steroidogenic tissues of Bmal1 KO mice. In particular, expression of the steroidogenic acute regulatory protein (StAR) gene and protein, which regulates the rate-limiting step of steroidogenesis, was decreased in testes from Bmal1 KO mice. A direct effect of BMAL1 on StAR expression in Leydig cells was indicated by in vitro experiments showing enhancement of StAR transcription by BMAL1 Other hormonal defects in male Bmal1 KO mice suggest that BMAL1 also has functions in reproductive physiology outside of the testis. These results enhance understanding of how the circadian clock regulates reproduction.