FOXP2-Regulated Signaling Pathways Critical for Higher Cognitive Functions

认知受损，特别是语言受损，是常见神经精神疾病的标志， 自闭症和精神分裂症;然而，更高认知功能的分子机制 人类的发展和进化仍然是未知的。信号通路的阐明， 对语言和认知的重要性将为未来的治疗提供目标。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被破坏。的 转录因子F0 XP 2是目前鉴定的唯一在分离的乳腺癌患者中突变的基因。 语言障碍，并且在发育中的人的额叶和纹状体区域都有高表达）。 个脑袋目前的数据支持F0 XP 2及其调节自闭症相关基因的作用， 精神分裂症， 本提案中的研究将集中在发育调节的下游信号通路， FbXP 2以及这些通路的干扰如何导致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F0 XP 2调控的信号通路， 这些通路中的哪些对于神经元分化和/或维持是重要的，2）确定 通过进行比较全基因， 人胎儿、恒河猴和小鼠脑中的转录组测序和F0 XP 2启动子结合， 和3）确定Fdxp 2和Foxpl如何在CNS发育期间协同调节基因表达， 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。

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 F0XP2 is the only gene currently identified that is mutated in patients with isolated language disturbances, and it has high expression in both frontal and striata) regions of developing human brain. Current data supports a role for both F0XP2 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 FbXP2 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 F0XP2 in human neurons, and which of these pathways are important for neuronal differentiation and/or maintenance, 2) Determine evolutionarily conserved and human-specific F0XP2 targets by conducting comparative whole gene transcriptome sequencing and F0XP2 promoter binding in fetal human, rhesus macaque, and mouse brain, and 3) Ascertain how Fdxp2 and Foxpl cooperatively regulate gene expression during CNS development by generating Foxpl conditional knockout mice and conducting genome wide Foxp2 promoter binding analysis.