The transcription factors SIX3 and VAX1 are required for suprachiasmatic nucleus circadian output and fertility in female mice,Journal of Neuroscience Research

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The transcription factors SIX3 and VAX1 are required for suprachiasmatic nucleus circadian output and fertility in female mice
Journal of Neuroscience Research ( IF 2.9 ) Pub Date : 2021-07-02 , DOI: 10.1002/jnr.24864
Hanne M Hoffmann _{1,

2,

3} , Jason D Meadows _{1,

2} , Joseph A Breuer _{1,

2} , Alexandra M Yaw ₃ , Duong Nguyen ₃ , Karen J Tonsfeldt _{1,

2} , Austin Y Chin _{1,

2} , Brooke M Devries ₃ , Crystal Trang _{1,

2} , Haley J Oosterhouse _{1,

2} , Jessica Sora Lee _{1,

2} , Jeffrey W Doser ₄ , Michael R Gorman _{2,

5} , David K Welsh _{2,

6,

7} , Pamela L Mellon _{1,

2}

Affiliation

The homeodomain transcription factors sine oculis homeobox 3 (Six3) and ventral anterior homeobox 1 (Vax1) are required for brain development. Their expression in specific brain areas is maintained in adulthood, where their functions are poorly understood. To identify the roles of Six3 and Vax1 in neurons, we conditionally deleted each gene using Synapsin^cre, a promoter targeting maturing neurons, and generated Six3^syn and Vax1^syn mice. Six3^syn and Vax1^syn females, but not males, had reduced fertility, due to impairment of the luteinizing hormone (LH) surge driving ovulation. In nocturnal rodents, the LH surge requires a precise timing signal from the brain's circadian pacemaker, the suprachiasmatic nucleus (SCN), near the time of activity onset. Indeed, both Six3^syn and Vax1^syn females had impaired rhythmic SCN output, which was associated with weakened Period 2 molecular clock function in both Six3^syn and Vax1^syn mice. These impairments were associated with a reduction of the SCN neuropeptide vasoactive intestinal peptide in Vax1^syn mice and a modest weakening of SCN timekeeping function in both Six3^syn and Vax1^syn mice. Changes in SCN function were associated with mistimed peak PER2::LUC expression in the SCN and pituitary in both Six3^syn and Vax1^syn females. Interestingly, Six3^syn ovaries presented reduced sensitivity to LH, causing reduced ovulation during superovulation. In conclusion, we have identified novel roles of the homeodomain transcription factors SIX3 and VAX1 in neurons, where they are required for proper molecular circadian clock function, SCN rhythmic output, and female fertility.

中文翻译：

转录因子 SIX3 和 VAX1 是雌性小鼠视交叉上核昼夜节律输出和生育能力所必需的

同源结构域转录因子正眼同源盒 3 (Six3) 和腹侧前同源盒 1 (Vax1) 是大脑发育所必需的。它们在特定大脑区域的表达在成年后仍保持不变，但人们对它们的功能知之甚少。为了确定Six3和Vax1在神经元中的作用，我们使用Synapsin ^cre （一种针对成熟神经元的启动子）有条件地删除每个基因，并生成Six3 ^syn和Vax1 ^syn小鼠。由于驱动排卵的黄体生成素 (LH) 激增受到损害， Six3 ^syn和Vax1 ^syn女性（而非男性）的生育能力降低。在夜间活动的啮齿类动物中，LH 激增需要在活动开始时大脑的昼夜节律起搏器（SCN）发出精确的定时信号。事实上， Six3 ^syn和Vax1 ^syn雌性小鼠的节律性 SCN 输出均受损，这与Six3 ^syn和Vax1 ^syn小鼠的第 2 期分子钟功能减弱有关。这些损伤与Vax1 ^syn小鼠中 SCN 神经肽血管活性肠肽的减少以及Six3 ^syn和Vax1 ^syn小鼠中 SCN 计时功能的适度减弱有关。在Six3 ^syn和Vax1 ^syn雌性中，SCN 功能的变化与 SCN 和垂体中 PER2::LUC 表达的峰值时间不合适有关。有趣的是， Six3^滑膜卵巢对 LH 的敏感性降低，导致超排卵期间排卵减少。总之，我们已经确定了同源域转录因子 SIX3 和 VAX1 在神经元中的新作用，它们是适当的分子生物钟功能、SCN 节律输出和女性生育能力所必需的。

更新日期：2021-07-02

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