The Role of Fox-1 in Neurodevelopment and Autistic Spectrum Disorder

自闭症谱系障碍（ASD）是一种神经发育状况，其定义为不同程度的自闭症。 社交、语言和行为障碍，每150名儿童中就有一名受到影响。最 严重的是自闭症症状在儿童早期出现，并导致严重的终身残疾。自闭症 有很强的遗传基础，但遗传学是复杂的，涉及多个基因的贡献， 以及环境因素。了解这种疾病的病因是重要的，无论是改善 临床治疗和诊断测试，以及了解人类神经发育。在这 关于这一点，研究导致自闭症的罕见突变成为一种强有力的手段， 神经发育途径和识别其组成部分。一个有趣的候选者是Fox-1基因 (also A2BP1）。一些证据表明Fox-1是一种重要的神经发育因子， 因子Fox-1是一种神经元特异性的选择性剪接调节因子，似乎在细胞凋亡中发挥重要作用。 人类和小鼠大脑中的基因表达。此外，四名患者已被确定为 Fox-1基因突变和ASD的特征，包括临床诊断为自闭症的患者。我们 假设Fox-1在早期人类神经发育过程中的基因表达中起关键作用， 会导致自闭症谱系障碍为了验证这一点，我们将1）识别基因， 使用剪接微阵列平台在人神经元细胞中通过Fox-1调节剪接。接下来我们将（2） 通过识别Fox-1依赖的可变剪接变化，将这些发现扩展到神经发育， 发生在人类神经元细胞分化为神经元的过程中。最后，我们将描述这个角色的特点 这些Fox-1靶基因在神经发育中的原位杂交， 一个合作项目的一部分，将其与鼠标开发相关联。该项目将改善我们的 了解神经发育过程中的基因调控，并促进对自闭症的进一步研究， 自闭症候选人对神经发育和神经退行性疾病以及 在分子生物学和RNA加工的坚实背景，这将通过经验加强 在人类遗传学、功能基因组学和生物信息学中的应用。该网站是一个富有成效的 学术机构，拥有广泛的神经科学社区，致力于职业发展， 候选人。导师是自闭症研究领域的领军人物，神经遗传学活跃 拥有所有遗传和分子研究工具的实验室。总的来说，这些资源提供了 为候选人过渡到作为科学调查员的独立角色提供最佳环境。 相关性（参见说明）： 自闭症谱系障碍被认为是美国主要的健康问题。估计有多达 大约有50万儿童患有某种形式的自闭症，其中大约四分之一的儿童患有临床自闭症。 自闭症和ASD可能会对患者及其家人产生毁灭性的影响，因为这种情况会导致 严重的终身残疾。这里提出的研究，检查了大脑特异性调节因子的作用， 神经发育中的基因表达，将扩展我们对导致ASD的原因的认识， 最终有助于更好地治疗，预防，甚至有一天治愈自闭症。

Autistic spectrum disorder (ASD) is a neurodevelopmental condition defined by variable degrees of impairment in socialization, language, and behavior which affects one out of every 150 children. The most severe form is autism. Symptoms present early in childhood and cause significant lifelong disability. Autism has a strong hereditary basis but the genetics are complex, involving contributions from multiple genes as well as environmental factors. Understanding the etiology of this disease is important, both for improving clinical treatments and diagnostic testing, as well as for understanding human neurodevelopment. In this regard, the study of rare mutations which lead to autism becomes a powerful means of identifying critical neurodevelopmental pathways and identifying their components. One intriguing candidate is the Fox-1 gene (also called A2BP1). Several lines of evidence suggest that Fox-1 is an important neurodevelopmental factor. Fox-1 is a neuron-specific regulator of alternative splicing that appears to play a significant role in gene expression in both human and mouse brain. Furthermore, four patients have been identified with mutations in the Fox-1 gene and features of ASD, including one with a clinical diagnosis of autism. We hypothesize that Fox-1 plays a key role in gene expression during early human neurodevelopment and that disruptions can lead to autistic spectrum disorder. To verify this, we will 1) identify genes whose alternative splicing is regulated by Fox-1 in human neuronal cells using a splicing microarray platform. Next we will 2) extend these findings to neurodevelopment by identifying Fox-1-dependent alternative splicing changes that occur during the differentiation of human neuronal cells to neurons. Finally, we will 3) characterize the role of these Fox-1 target genes in neurodevelopment using in situ hybridization in human fetal brain and, as part of a collaborative project, correlate this to mouse development. This project will improve our understanding of gene regulation during neurodevelopment and stimulate further studies of autism and ASD. The candidate has a strong interest in neurodevelopmental and neurodegenerative disease as well as a solid background in molecular biology and RNA processing which will be strengthened by the experience in human genetics, functional genomics, and bioinformatics proposed here. The site is a productive academic institution, with an extensive neuroscience community, committed to the career development of the candidate. The mentor is a leader in the field of autism research and has an active neurogenetics laboratory with all the tools for genetic and molecular research. Overall, these resources provide the optimum environment for the candidate to transition into an independent role as a scientific investigator. RELEVANCE (See instructions): Autistic spectrum disorder is being recognized as a major US health concern. It is estimated that up to 500,000 children experience some form of this condition, with perhaps one-quarter having clinical autism. Autism and ASD can have a devastating impact on patients and their families as the condition leads to significant life-long disability. The studies proposed here, examining the role a brain-specific regulator of gene expression in neurodevelopment, will extend our knowledge of what can cause ASD and may ultimately help to better treat, prevent, or someday even cure autism.