Arx Associated Transcriptional Networks in Neocortical Development

项目摘要 神经发育障碍（智力残疾、癫痫、自闭症、注意力缺陷等）是 根据疾病控制中心的报告，美国每6名儿童中就有1人被诊断出患有这种疾病， 预防尽管发病率很高，但只有少数疾病的分子和细胞基础 已经阐明，大多数的基础仍然未知。有意思的是， ARX几乎展示了所有这些特性。然而，ARX的发育机制 突变导致的这一系列问题尚未完全了解。我们之前的工作 表明ARX在两种不同的神经祖细胞群体中表达， 它在每个种群中通过调节不同的细胞亚群发挥不同的作用。 基因.此外，我们已经表明，每个祖细胞群体中Arx的丢失解释了 小鼠和人类表型的特定组分。在这项提案中，根据我们从 在过去的十年里，我们试图了解ARX如何调节不同基因的不同子集， 祖先群体首先，拟议的研究将集中在识别ARX相互作用 转录因子（或辅因子）及其下游靶基因在每个细胞中由ARX共调控， 细胞群蛋白质组学和基因组学的结合， 网络分析将确定预测在每个祖细胞中起关键作用的关键靶基因 我们之前定义的特定的ARX介导的细胞功能。第二，建议的研究 将阐明ARX和ARX相关网络影响皮质神经元的机制。 祖细胞增殖和模式化。第三，拟议的研究将描述ARX的作用， GE祖细胞发育中的ARX相关网络。这些研究预计将提供 更好地了解ARX如何在正常和异常的大脑发育中发挥作用， 有助于我们了解儿童常见疾病的发病机制， 智力残疾、癫痫、自闭症和大脑结构异常。

PROJECT SUMMARY Neurodevelopmental disorders (intellectual disability, epilepsy, autism, attention deficit, etc.) are diagnosed in 1 in 6 children in the US according to the report from the Center for Disease Control and Prevention. Despite this high frequency, the molecular and cellular basis for only a few disorders have been elucidated, the basis of most remains unknown. Interestingly, patients with mutations in ARX exhibit nearly all of these features. However, the developmental mechanism by which ARX mutations result in this wide spectrum of problems is incompletely understood. Our prior work has demonstrated that ARX is expressed in two different neural progenitor populations during forebrain development and that it plays distinct roles in each population by regulating different subsets of genes. Furthermore, we have shown that the loss of Arx from each progenitor population accounts for specific components of the mouse and human phenotypes. In this proposal, building on our data from the past ten years, we seek to understand how ARX regulates different subset of genes in different progenitor populations. First, the proposed studies will focus on identification of ARX-interacting transcription factors (or co-factors) and their down-stream target genes co-regulated by ARX in each cell population. The combination of proteomics and genomics approach as well as systematic network analysis will identify the key target genes predicted to play crucial roles in each progenitor specific, ARX-mediated cellular functions that we previously defined. Second, the proposed studies will elucidate the mechanism(s) by which ARX and ARX-associated network influence cortical progenitor proliferation and patterning. Third, the proposed studies will delineate the role of ARX and ARX-associated network in GE progenitor cell development. These studies are expected to provide a greater understanding of how ARX functions in normal and abnormal brain development, and will contribute to our understanding of the pathogenesis of such common disorders in children as intellectual disabilities, epilepsy, autism, and structural anomalies of the brain.