FOXP2-Regulated Signaling Pathways Critical for Higher Cognitive Functions

描述(申请人提供)：认知受损，特别是语言障碍，是自闭症和精神分裂症等常见神经精神疾病的特征；然而，人类高级认知功能发育和进化的分子机制仍不清楚。阐明对语言和认知很重要的信号通路将为未来的治疗提供靶点。额叶-纹状体回路是正常认知功能的关键，在神经精神疾病中经常被破坏。转录因子FOXP2是目前发现的唯一在孤立性语言障碍患者中发生突变的基因，它在发育中的人脑的额叶和纹状体区域都有高表达。目前的数据支持FOXP2及其对自闭症和精神分裂症相关基因的调控。这项提案中的研究将集中在FOXP2下游发育调节的信号通路，以及这些通路的扰动如何导致自闭症和精神分裂症的认知缺陷。其具体目标包括：1)确定FOXP2在人神经元中调控的信号通路，以及这些通路中哪些对于神经元的分化和/或维持是重要的；2)通过在胎儿、猕猴和小鼠脑中进行比较全基因转录组测序和FOXP2启动子结合，确定进化上保守的和人类特有的FOXP2靶点；以及3)通过建立Foxp1条件基因敲除小鼠并进行全基因组Foxp2启动子结合分析，确定Foxp2和Foxp1如何在中枢神经系统发育过程中协同调节基因表达。这项建议包含了详细的五年培训计划和研究建议，概述了首席研究员如何掌握最新技术的新技能，完成当前的研究，为独立研究奠定基础，并过渡到独立的研究人员职位，研究神经精神疾病的分子遗传学。首席研究员是一位熟练的分子和细胞神经生物学家，曾接受过动物模型和基因表达数据生物信息学分析方面的培训。在丹尼尔·格施温德博士的指导下，首席研究员将学习和实施下一代测序技术。格施温德博士是神经遗传学领域的国际知名领导者，尤其是自闭症遗传学，他的实验室发表了大量关于大脑基因表达研究的复杂分析。此外，一个由加州大学洛杉矶分校杰出教职员工组成的咨询委员会将提供科学和职业指导。加州大学洛杉矶分校神经病学和脑研究所将共同提供成功完成这项培训计划所需的所有资源，包括备受尊敬的科学家、核心设施和活跃的教学社区。 公共卫生相关性：自闭症谱系障碍和精神分裂症是美国和世界范围内最常见的两种认知障碍。正确的大脑发育对认知至关重要，这些发育过程很容易受到干扰，从而导致精神疾病。这些拟议的研究将提供对认知潜在的发展机制的洞察，以及它们在精神疾病中是如何被破坏的。

DESCRIPTION (provided by applicant): Impaired cognition, and in particular language, is a hallmark of common neuropsychiatric diseases such as autism and schizophrenia; however, the molecular mechanisms underlying higher cognitive function development and evolution in humans remain unknown. The elucidation of signaling pathways that are important for language and cognition will provide targets for future therapeutics. Frontal-striatal circuitry is critical for normal cognitive function and is frequently disrupted in neuropsychiatric disease. The transcription factor FOXP2 is the only gene currently identified that is mutated in patients with isolated language disturbances, and it has high expression in both frontal and striatal regions of developing human brain. Current data supports a role for both FOXP2 and its regulation of genes involved in autism and schizophrenia. The research in this proposal will focus on the developmentally regulated signaling pathways downstream of FOXP2 and how perturbations to these pathways result in cognitive defects in both ASD and schizophrenia. The specific aims include: 1) Identify the signaling pathways regulated by FOXP2 in human neurons, and which of these pathways are important for neuronal differentiation and/or maintenance, 2) Determine evolutionarily conserved and human-specific FOXP2 targets by conducting comparative whole gene transcriptome sequencing and FOXP2 promoter binding in fetal human, rhesus macaque, and mouse brain, and 3) Ascertain how Foxp2 and Foxp1 cooperatively regulate gene expression during CNS development by generating Foxp1 conditional knockout mice and conducting genome wide Foxp2 promoter binding analysis. This proposal contains a detailed five year training plan and research proposal outlining how the principle investigator will acquire new skills in recent technology, complete current studies, lay the foundation for independent studies, and transition to an independent investigator position to study the molecular genetics of neuropsychiatric illnesses. The principle investigator is a skilled molecular and cell neurobiologist with training in animal models and bioinformatic analysis of gene expression data. Under the mentorship of Dr. Daniel Geschwind, the principle investigator will learn and implement next generation sequencing technologies. Dr. Geschwind is an internationally renowned leader in the field of neurogenetics, in particular autism genetics, and his laboratory has published extensively on complex analysis of brain gene expression studies. In addition, an advisory committee of distinguished UCLA faculty members will provide scientific and career guidance. Together, the Department of Neurology and Brain Research Institute at UCLA will provide all of the resources needed to successfully complete this training plan including highly regarded scientists, core facilities, and an active didactic community. PUBLIC HEALTH RELEVANCE: Autism spectrum disorders and schizophrenia are two of the most common cognitive disorders in the United States and worldwide. Proper brain development is critical for cognition and these developmental processes are vulnerable to disruptions, which subsequently lead to mental illness. These proposed studies will provide insight into the developmental mechanisms underlying cognition and how they are disrupted in mental illness.