FOXP2-Regulated Signaling Pathways Critical for Higher Cognitive Functions

认知受损，尤其是语言障碍，是常见神经精神疾病的标志，如 自闭症和精神分裂症；然而，高级认知功能背后的分子机制 人类的发展和进化仍然未知。信号转导途径的阐明 对语言和认知的重要作用将为未来的治疗提供靶点。额叶-纹状体回路是 对正常的认知功能至关重要，在神经精神疾病中经常受到干扰。这个 转录因子F0XP2是目前发现的唯一在孤立性结肠炎患者中发生突变的基因 语言障碍，在人类发育期的额叶和纹状体都有高表达 大脑。目前的数据支持F0XP2及其对自闭症相关基因和 精神分裂症， 这项建议中的研究将集中在发育调节的信号通路下游 FbXP2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， 具体目标包括：1)确定F0XP2在人神经元中调控的信号通路，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)确定 通过比较全基因获得进化上保守的和人类特异的F0XP2靶点 胎儿、恒河猴和小鼠脑的转录组测序和F0XP2启动子结合， 3)确定Fdxp2和Foxp1在中枢神经系统发育过程中如何协同调节基因表达 建立Foxp1条件性基因敲除小鼠并进行全基因组Foxp2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.