Analysis of MeCP2 function in neural crest derivatives

描述（由申请人提供）：Rett综合征（RTT）是由甲基- cpg结合蛋白2 （MECP2）突变引起的显性x连锁神经发育障碍。受影响的患者有各种各样的自主神经异常，这些异常会对这些个体的生活质量产生不利影响，并可能导致RTT患者亚群容易突然意外死亡。完全缺乏MeCP2功能（Mecp2null/Y）的雄性小鼠再现了RTT的许多特征，包括呼吸异常和便秘。从Wnt-1表达域的神经嵴衍生物中去除MeCP2功能可再现Mecp2null/Y小鼠的致病性。该假说认为，Wnt-1结构域MeCP2功能的缺失导致自主神经功能障碍，最终导致早期死亡。为了研究神经嵴源性组织在RTT发病过程中自主神经功能障碍中的作用，我计划进行以下实验。我将详细描述这些动物的自主神经功能以及神经嵴衍生物的细胞组成，特别关注交感神经节。此外，我将使用遗传技术在缺乏MeCP2功能的动物的神经嵴中引入MeCP2功能，并确定这是否足以恢复正常的寿命和自主神经功能。本提案中概述的研究旨在了解Mecp2null/Y小鼠中观察到的自主神经功能障碍和早期死亡的原因。最终，这种理解将有助于为患有RTT的女孩开发治疗方案，并为自主控制的神经机制提供见解。

DESCRIPTION (provided by applicant): Rett Syndrome (RTT) is a dominant X-linked neurodevelopment disorder caused by mutation of Methyl- CpG-binding Protein 2 (MECP2). Affected patients have a variety of autonomic abnormalities that adversely affect quality of life for these individuals and likely contribute to the sub-population of RTT patients prone to sudden unexpected death. Male mice that completely lack MeCP2 function (Mecp2null/Y) reproduce many features of RTT including breathing abnormalities and constipation. Removing MeCP2 function from neural crest derivatives in the Wnt-1 expression domain reproduces the lethality observed in Mecp2null/Y mice. The hypothesis of this proposal is that dismption of MeCP2 function in the Wnt-1 domain causes autonomic dysfunction which ultimately leads to early death. To address the role of neural crest derived tissue in autonomic dysfunction during RTT pathogenesis, I plan the following experiments. I will perform detailed characterization of both the autonomic function in these animals as well as the cellular composition of the neural crest derivatives, with particular focus on the sympathetic ganglia. Additionally, I will use genetic techniques to introduce MeCP2 function in the neural crest of animals that otherwise lack MeCP2 function and determine if this is sufficient to restore normal lifespan and autonomic function. The research outlined in this proposal seeks to understand the causes of both the autonomic dysfunction as well as the early lethality observed in Mecp2null/Y mice. Ultimately, this understanding will help both develop therapeutic options for girls with RTT as well as provide insight into the neural mechanisms of autonomic control.