FOXP2-Regulated Signaling Pathways Critical for Higher Cognitive Functions

描述（由申请人提供）：认知受损，特别是语言受损，是常见神经精神疾病（如自闭症和精神分裂症）的标志;然而，人类高级认知功能发育和进化的分子机制仍然未知。对语言和认知重要的信号通路的阐明将为未来的治疗提供靶点。额叶-纹状体回路对正常认知功能至关重要，在神经精神疾病中经常受到破坏。转录因子FOXP 2是目前发现的唯一一个在孤立的语言障碍患者中突变的基因，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FOXP 2及其对自闭症和精神分裂症相关基因的调节作用。该提案中的研究将集中在FOXP 2下游的发育调节信号通路以及这些通路的扰动如何导致ASD和精神分裂症的认知缺陷。具体目标包括：1）鉴定人神经元中由FOXP 2调节的信号传导途径，以及这些途径中的哪些对于神经元分化和/或维持是重要的，2）通过在胎儿人、恒河猴和小鼠脑中进行比较性全基因转录组测序和FOXP 2启动子结合来确定进化上保守的和人特异性的FOXP 2靶标，和3）通过产生Foxp 1条件性敲除小鼠并进行全基因组Foxp 2启动子结合分析，确定Foxp 2和Foxp 1如何在CNS发育期间协同调节基因表达。该提案包含一个详细的五年培训计划和研究提案，概述了主要研究者将如何获得最新技术的新技能，完成当前的研究，为独立研究奠定基础，并过渡到独立研究者职位，研究神经精神疾病的分子遗传学。主要研究者是一位熟练的分子和细胞神经生物学家，接受过动物模型和基因表达数据生物信息学分析的培训。在丹尼尔Geschwind博士的指导下，主要研究人员将学习和实施下一代测序技术。Geschwind博士是神经遗传学领域的国际知名领导者，特别是自闭症遗传学，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师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系和脑研究所将共同提供成功完成该培训计划所需的所有资源，包括备受推崇的科学家，核心设施和积极的教学社区。 公共卫生相关性：自闭症谱系障碍和精神分裂症是美国和全世界最常见的两种认知障碍。适当的大脑发育对认知至关重要，这些发育过程容易受到干扰，从而导致精神疾病。这些拟议中的研究将深入了解认知的发展机制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.