Arx Associated Transcriptional Networks in Neocortical Development

项目总结 神经发育障碍(智力残疾、癫痫、自闭症、注意力缺陷等)是 根据美国疾病控制和预防中心的报告，美国每6名儿童中就有1人被诊断出 预防。尽管频率很高，但只有少数疾病的分子和细胞基础 虽然已被阐明，但大多数的基础仍不清楚。有趣的是，携带基因突变的患者 ARX几乎展示了所有这些功能。然而，ARX的发育机制 突变导致了如此广泛的问题还没有完全被理解。我们之前的工作是 证明ARX在前脑的两个不同的神经前体群体中表达 它通过调节不同的子集在每个种群中发挥着不同的作用 基因。此外，我们已经证明，每个祖代群体中Arx的丢失解释了 老鼠和人类表型的特定成分。在这份提案中，基于我们来自 在过去的十年里，我们试图了解ARX是如何在不同的基因中调节不同的子集的 祖代种群。首先，拟议的研究将集中在ARX相互作用的鉴定上 转录因子(或辅助因子)及其下游靶基因受ARX共同调控 细胞数量。蛋白质组学与基因组学相结合的方法以及系统化 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，拟进行的研究 将阐明ARX和ARX相关网络影响大脑皮质的机制(S) 祖细胞增殖和图案化。第三，拟议的研究将描绘ARX和ARX的作用 ARX相关网络在GE祖细胞发育中的作用这些研究有望提供一种 更好地了解ARX如何在正常和异常的大脑发育中发挥作用，以及 有助于我们理解儿童常见疾病的发病机制，如 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.