Department of Reproductive Medicine and Center for Reproductive Science and Medicine, University of California, San Diego, La Jolla, California 92093-0674, USA.
J Neurosci. 2011 Jan 12;31(2):426-38. doi: 10.1523/JNEUROSCI.1688-10.2011.
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.
下丘脑、垂体和性腺协调一致，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）神经元从鼻基板正确迁移到下丘脑，然后是 GnRH 的适当合成和脉冲分泌，而在下性腺功能减退症患者中这些功能缺失。在这项研究中，我们确定 sine oculis-related homeobox 6（Six6）是一种新的必需因素，可将 GnRH 表达正确靶向到成年小鼠下丘脑有限数量的 GnRH 神经元中，并证明它是雄性和雌性小鼠正常生殖功能所必需的。雌性 Six6 缺失小鼠的生育能力明显下降，无法正常通过发情周期，没有任何成功排卵的迹象，也无法产仔。尽管这些小鼠的基础促性腺激素生成相对正常，但对 GnRH 表达的分析显示 GnRH 神经元总数明显减少。我们表明，Six6 的表达在 GnRH 神经元成熟过程中显著增加，并且 Six6 的过表达可诱导神经元细胞中的 GnRH 转录。最后，我们证明这种 GnRH 表达的诱导是通过 Six6 与位于 GnRH 近端启动子内的进化上保守的 ATTA 位点结合介导的。这些数据表明，Six6 在 GnRH 表达的调节和下丘脑对生育能力的控制中发挥重要作用。
