The role of Foxp1-regulated signaling pathways in brain development and behavior

 描述（由申请人提供）：大脑发育的信号通路的完整知识仍然未知。我们实验室的长期目标是阐明在神经发育障碍中被破坏的分子信号通路，这些通路对大脑发育很重要。编码FOXP 1的基因突变先前已在发育迟缓、智力残疾和自闭症的个体中发现。我们的初步研究表明，转录因子FOXP 1调节大脑发育中重要的基因，FOXP 1水平的降低会导致啮齿动物的行为变化。此外，我们的数据表明，Foxp 1是神经元活动重要基因的关键调节因子 Foxp 1的缺失导致神经元功能改变。基于这些数据，推动这一提议的中心假设是FOXP 1是转录信号级联的协调者，这些级联对神经元功能很重要，并且在神经发育障碍如ASD中有风险。我们建议通过使用啮齿动物模型和人类转录组数据的组合，通过三个具体目标来确定发育中的大脑中FOXP 1的发育和区域疾病相关靶点：1）确定大脑中由Foxp 1调控的发育转录程序; 2）评估Foxp 1和靶基因在活动依赖性神经元功能中的作用;以及3）确定大脑中Foxp 1对特定ASD相关行为的区域贡献。总之，这些目标将确定Foxp 1在整个大脑发育过程中调控的转录程序，以及Foxp 1基因调控如何与神经元功能和特定疾病相关行为相关。完成拟议的目标将提供更多的知识，以分子途径，可以有针对性地治疗自闭症的个人。所产生的啮齿动物模型可用于研究逆转自闭症相关行为的新治疗方法。这些数据还将提供对控制正常大脑发育的基本分子机制的深入了解。

 DESCRIPTION (provided by applicant): Complete knowledge of the signaling pathways underlying brain development still remains unknown. The long- term goal of our laboratory is to elucidate the molecular signaling pathways disrupted in neurodevelopmental disorders that are important for brain development. Mutations in the gene encoding FOXP1 have previously been identified in individuals with developmental delay, intellectual disability, and autism. Our preliminary studies have shown that the transcription factor FOXP1 regulates genes important in brain development, and reduction in FOXP1 levels leads to behavioral changes in rodents. In addition, our data show that Foxp1 is a critical regulator of genes important for neuronal activity and loss of Foxp1 results in altered neuronal function. Based on these data, the central hypothesis driving this proposal is that FOXP1 is an orchestrator of transcriptional signaling cascades that are important for neuronal function and are at risk in neurodevelopmental disorders such as ASD. We propose to identify the developmental and regional disease-relevant targets of FOXP1 in the developing brain by using a combination of rodent models and human transcriptome data through three specific aims: 1) Identify the developmental transcriptional program regulated by Foxp1 in the brain; 2) Assess the role of Foxp1 and target genes in activity-dependent neuronal function; and 3) Determine the regional contribution of Foxp1 in the brain to specific ASD-relevant behaviors. Together, these aims will determine the transcriptional program regulated by Foxp1 throughout brain development and how Foxp1 gene regulation may be related to neuronal function and specific disease- relevant behaviors. Completion of the proposed aims will provide increased knowledge as to the molecular pathways that can be targeted for treatment in individuals with autism. The generated rodent models can be utilized to examine new therapeutic approaches for reversing autism-relevant behaviors. These data will also provide insight into the basic molecular mechanisms governing normal brain development.