Neurobiology of MeCP2 in adult neurogenesis

Rett综合征(RTT)是一种X连锁的显性疾病，由基因功能丧失突变引起 编码甲基CpG结合蛋白2(MECP2)。人类患者样本和动物模型的研究 提示MECP2/MeCP2可能在神经元成熟和突触中起重要作用 在开发过程中形成/维护。MeCP2在神经元发育中的神经生物学研究进展 在海马齿状突触中，不断地有新的颗粒神经元。 在所有被研究的哺乳动物中，包括人类在内的所有哺乳动物一生中都是由神经前体产生的。成虫 海马神经发生受到生理和病理刺激的动态调节，并被认为是 参与特定的大脑功能，如学习和记忆。成人神经发生缺陷也有 与某些脑部疾病有关。成人神经发生重述完整的神经元 成熟脑环境中的发育过程，包括神经的增殖和命运指定 祖细胞，神经元形态发生，迁移，轴突和树突发育，以及突触 神经元后代的发育。我们最近的研究和其他研究表明，大脑中的神经元发育 成人大脑遵循一个刻板印象的模式，达到与胚胎神经发生相同的里程碑，但 成体神经元的整合过程明显延长。如此千篇一律、久拖不决 单个神经元亚型(齿状颗粒细胞)在相对稳定状态下的发育过程 成熟的大脑提供了一种独特的模型系统来研究在体神经元发育的机制 非常详细。我们开发了一种“单细胞遗传学”方法来研究新生儿的发育。 利用免疫细胞化学、多光子共聚焦显微镜、 电子显微镜和电生理学。在当前的项目中，我们的目标是检查角色和了解 MeCP2在生后海马神经发生中的作用机制 调节脑内GABA能和谷氨酸能突触的形成、成熟和维持 成人大脑中的新神经元。我们的项目，非常详细地解决了MeCP2的细胞自主角色 在活体内，将从独特的角度为整个中心的主要目标理解 RTT的分子基础。这些研究的结果将与嗅觉的结果进行交叉比较。 系统(项目2)阐明MeCP2在不同疾病中神经元功能的异同 发育阶段和大脑区域。MECP2的随机X失活在女性中发生，甚至在 具有良好的X失活偏斜和WT MECP2等位基因的优势表达 学习障碍。我们的模型系统检测正常的MeCP2功能障碍的单个神经元 因此，神经环境对RTT的病理生理学和病因学具有重要的临床意义。 此外，RTT通常在6-18个月龄时表现为远远超出初级神经发生，我们的 因此，对MeCP2在出生后神经发生中的功能作用的研究可能会提供更多的新见解。 更重要的是，这种体内系统为探索药理学和行为学提供了一个平台 最终可应用于人类以克服这种大脑障碍的治疗方法(项目 1)，中心的最终目标。 相关性(请参阅安装)：

Rett syndrome (RTT) is an X-linked dominant disorder caused by loss-of-function mutations in the gene encoding methyl CpG binding protein 2 (MECP2). Studies of human patient samples and animal models suggest that MECP2/MeCP2 may play essential roles In neuronal maturation and synapse formation/maintenance during development. The neurobiology of MeCP2 in neuronal development remains to be fully characterized, in the dentate gynjs of the hippocampus, new granule neurons are continuously generated from neural progenitors throughout life in all mammals examined, including humans. Adult hippocampal neurogenesis is dynamically regulated by physiological and pathological stimuli and believed to be involved in specific brain functions, such as leaming and memory. Defect in adult neurogenesis has also been implicated in certain brain disorders. Adult neurogenesis recapitulates the complete neuronal developmental process in a mature brain environment, including proliferation and fate specification of neural progenitors, neuronal morphogenesis, migration, axon and dendritic development, and synapse development by neuronal progeny. Our recent studies and others showed that neuronal development in the adult brain follows a stereotypic pattern in reaching same milestones as in embryonic neurogenesis, yet the integration process for adult-born neuron is significantly prolonged. Such a stereotypic and prolonged development process for a single neuronal subtype (dentate granule cell) in a relative "steady-state" of mature brain offers a unique model system to investigate mechanisms of neuronal development in vivo in a great detail. We have developed a "single-cell genetic' approach for studying the development of newborn granule cells in vivo using a combination of immunocytochemistry, multi-photon confocal microscopy, electron microscopy and electrophysiology. In the cun-ent project, we aim to examine the role and underiying mechanisms of MeCP2 in postnatal hippocampal neurogenesis in vivo with the following hypothesis: MeCP2 regulates the formation, maturation and maintenance of GABAergic and glutamatergic synapses of new neurons in the adult brain. Our project, addressing in great detail the cell autonomous roles of MeCP2 in vivo, will contribute from a unique aspect to the main goal of the whole center in understanding the molecular basis of RTT. Findings from these studies will be cross-compared with those from the olfactory system (Project 2) to elucidate similarities and differences of neuronal functions of MeCP2 in different developmental stages and brain regions. Random X-inactivation of MECP2 occurs in female and even those with favorable skewing of X inactivation and predominant expression of the WT MECP2 allele exhibit learning disability. Our model system examining individual neurons with MeCP2 dysfuncl^tion in a normal neuronal environment thus have significant clinical implications for the pathophysiology and etiology of RTT. n addition, RTT normally manifests at 6-18 months of age well beyond the primary neurogenesis, our studies of functional roles of MeCP2 in postnatal neurogenesis may thus provide additional novel insights. More importantly, such in vivo system provides a platform for exploring pharmacological and behavioral therapeutic approaches that can be eventually applied in humans to overcome such brain disorder (Project 1), the ultimate goal of the center. RELEVANCE (See instaictions):