Genetic analyses of Arx homeobox gene function in neurodevelopmental disorders

描述（由申请人提供）：影响神经发育障碍（如自闭症）的遗传网络知之甚少。虽然一些基因突变与自闭症和智力迟钝综合症有关，但受这些突变影响的发育过程以及这些基因发挥作用的调控途径在很大程度上是未知的。x连锁的人类Arx同源盒基因的不同突变与一系列发育障碍有关，从皮质畸形到与自闭症相关的行为功能障碍。敲除Arx的雄性小鼠也表现出与最严重的人类疾病一致的大脑结构缺陷，表明Arx在这两个物种中的作用相似。有趣的是，我们最近发现，秀丽隐杆线虫的Arx同源基因al -1的突变会影响相关的发育过程，这表明基因功能在门间具有显著的保守性。我们建议利用小鼠和秀丽隐杆线虫模型系统中独特的实验工具来进一步研究ARX功能。具体来说，我们将：1。利用小鼠和秀丽隐杆线虫系统探索与特定神经发育障碍相关的Arx突变对神经元发育和功能的影响。2. 探索在秀丽隐杆线虫中被鉴定为ALR-1相互作用因子的ARX和COUP转录因子在小鼠神经元发育中的功能相互作用。3. 利用秀丽隐杆线虫的遗传能力，快速识别ARX相互作用物、调节物和靶点，并开始探索其小鼠同源物在ARX介导的神经元发育中的作用。这些利用两个模型系统并行进行的实验将极大地扩展我们对Arx基因功能的理解，并确定未来治疗干预的潜在靶点。Arx同源盒基因的突变会导致广泛的神经发育障碍，如自闭症和智力迟钝。我们将利用小鼠和秀丽隐杆线虫两种实验系统的独特优势，研究Arx基因突变如何影响大脑发育。这项工作可能使我们能够快速确定合理药物设计的潜在新靶点。

DESCRIPTION (provided by applicant): The genetic networks affected in neurodevelopmental disorders such as autism are poorly understood. Although mutations in several genes have been linked to autism and mental retardation syndromes, the developmental processes affected by these mutations, and the regulatory pathways in which these genes function are largely unknown. Different mutations in the X-linked human Arx homeobox gene have been associated with a range of developmental disorders from cortical malformations to behavioral dysfunction linked to autism. The Arx knockout male mouse also exhibits defects in brain structure consistent with the most severe human disorders, indicating that ARX acts similarly in these two species. Interestingly, we have recently shown that mutations in alr-1, the C. elegans ortholog of Arx affect related developmental processes, suggesting a remarkable conservation of gene function across phyla. We propose to take advantage of the unique experimental tools available in the mouse and C. elegans model systems to further investigate ARX functions. Specifically, we will: 1. Explore the effects of Arx mutations associated with specific neurodevelopmental disorders on neuronal development and function using both the mouse and C. elegans systems. 2. Explore the functional interactions between ARX and a COUP transcription factor identified as an ALR-1 interactor in C. elegans on neuronal development in the mouse. 3. Exploit the genetic power of C. elegans to rapidly identify ARX interactors, regulators and targets, and begin to explore the roles of their mouse homologs in ARX-mediated neuronal development. These experiments utilizing two model systems in parallel will greatly and rapidly expand our understanding of Arx gene function, and identify potential targets for future therapeutic intervention. Mutations in the Arx homeobox gene result in a wide range of neurodevelopmental disorders such as autism and mental retardation. We will exploit the unique advantages of two experimental systems, the mouse and C. elegans, to investigate how Arx gene mutations affect brain development. This work may allow us to rapidly identify potential new targets for rational drug design.