Hypothalamic dysregulation and infertility in mice lacking the homeodomain protein Six6.
Hypothalamic dysregulation and infertility in mice lacking the homeodomain protein Six6.
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DOI：
10.1523/jneurosci.1688-10.2011
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发表时间：
2011-01-12
期刊：
影响因子：
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通讯作者：
Mellon PL
中科院分区：
文献类型：
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作者：
Larder R;Clark DD;Miller NL;Mellon PL
下丘脑、垂体和性腺协调指导哺乳动物生殖功能的发育和调节。下丘脑-垂体-性腺轴的控制依赖于促性腺激素释放激素（GnRH）神经元从鼻基板到下丘脑的正确迁移，然后是GnRH的适当合成和脉冲式分泌，性腺功能减退性性腺功能减退症患者缺乏这种功能。在这项研究中，我们确定sine oculis-related homeobox 6（Six 6）作为一种新的必要因素，适当的目标GnRH表达的有限人口的GnRH神经元内的成年小鼠下丘脑，并证明它是需要适当的生殖功能在男性和女性小鼠。雌性Six 6-null小鼠表现出生育力的显著降低，不能正常地通过发情周期，显示出成功排卵的任何迹象，或产生窝仔。虽然这些小鼠的基础促性腺激素产生相对正常，但GnRH表达分析显示总GnRH神经元数量急剧减少。我们发现，在GnRH神经元成熟过程中，Six 6的表达显著增加，并且Six 6的过表达诱导神经元细胞中的GnRH转录。最后，我们证明，这种诱导GnRH表达介导的Six 6进化保守的ATTA位点位于GnRH近端启动子内的结合。总之，这些数据表明Six 6在调节GnRH表达和下丘脑控制生育方面起着重要作用。
The hypothalamus, pituitary, and gonads coordinate to direct the development and regulation of reproductive function in mammals. Control of the hypothalamic–pituitary– gonadal axis is dependent on correct migration of gonadotropin-releasing hormone (GnRH) neurons from the nasal placode to the hypothalamus, followed by proper synthesis and pulsatile secretion of GnRH, functions absent in patients with hypogonadal hypogonadism. In this study, we identify sine oculis-related homeobox 6 (Six6) as a novel factor necessary for proper targeting of GnRH expression to the limited population of GnRH neurons within the adult mouse hypothalamus and demonstrate that it is required for proper reproductive function in both male and female mice. Female Six6-null mice exhibit a striking decrease in fertility, failing to progress through the estrous cycle normally, show any signs of successful ovulation, or produce litters. Although basal gonadotropin production in these mice is relatively normal, analysis of GnRH expression reveals a dramatic decrease in total GnRH neuron numbers. We show that expression of Six6 is dramatically increased during GnRH neuronal maturation and that overexpression of Six6 induces GnRH transcription in neuronal cells. Finally, we demonstrate that this induction in GnRH expression is mediated via binding of Six6 to evolutionarily conserved ATTA sites located within the GnRH proximal promoter. Together, these data indicate that Six6 plays an important role in the regulation of GnRH expression and hypothalamic control of fertility.