Jan and Dan Duncan Neurological Research Institute, Houston, Texas 77030, USA.
J Neurosci. 2011 Jul 13;31(28):10359-70. doi: 10.1523/JNEUROSCI.0057-11.2011.
Rett syndrome is a neurodevelopmental disorder caused by mutations in methyl-CpG-binding protein 2 (MECP2), a transcriptional regulator. In addition to cognitive, communication, and motor problems, affected individuals have abnormalities in autonomic function and respiratory control that may contribute to premature lethality. Mice lacking Mecp2 die early and recapitulate the autonomic and respiratory phenotypes seen in humans. The association of autonomic and respiratory deficits with premature death suggests that Mecp2 is critical within autonomic and respiratory control centers for survival. To test this, we compared the autonomic and respiratory phenotypes of mice with a null allele of Mecp2 to mice with Mecp2 removed from their brainstem and spinal cord. We found that MeCP2 is necessary within the brainstem and spinal cord for normal lifespan, normal control of heart rate, and respiratory response to hypoxia. Restoration of MeCP2 in a subset of the cells in this same region is sufficient to rescue abnormal heart rate and abnormal respiratory response to hypoxia. Furthermore, restoring MeCP2 function in neural centers critical for autonomic and respiratory function alleviates the lethality associated with loss of MeCP2 function, supporting the notion of targeted therapy toward treating Rett syndrome.
雷特综合征是一种神经发育障碍，由甲基化CpG 结合蛋白 2（MECP2）基因突变引起，MECP2 是一种转录调节因子。除了认知、沟通和运动问题外，受影响的个体还存在自主功能和呼吸控制异常，这可能导致过早死亡。缺乏 Mecp2 的小鼠会早期死亡，并重现人类所见的自主和呼吸表型。自主和呼吸功能缺陷与过早死亡的关联表明，Mecp2 在自主和呼吸控制中心对于生存至关重要。为了验证这一点，我们比较了具有 Mecp2 缺失等位基因的小鼠与脑和脊髓中去除 Mecp2 的小鼠的自主和呼吸表型。我们发现，MeCP2 对于正常寿命、正常心率控制以及对缺氧的呼吸反应是必需的，位于脑干和脊髓中。在同一区域的一部分细胞中恢复 MeCP2 足以挽救异常的心率和对缺氧的异常呼吸反应。此外，在自主和呼吸功能关键的神经中枢恢复 MeCP2 功能可以减轻与 MeCP2 功能丧失相关的致死性，支持针对治疗雷特综合征的靶向治疗的概念。
