Studying the Molecular Mechanism of Foxp1/2 Function Controlling the Cerebellar Development

项目总结/摘要 编码叉头盒转录因子的FOXP 1和FOXP 2的突变与自闭症有关， 智力迟钝和语言障碍。在动物模型中的功能研究已经证明 FoxPs在CNS，特别是前脑发育中的组合作用。然而，一个明确的 对它们的功能机制缺乏了解。我们最近发现， 在小鼠中，浦肯野细胞（PC）的异质群体表达Foxp 1、2和4的不同组合 胚胎小脑通过小脑特异性基因敲除实验，我们发现Foxp 1或Foxp 2的缺失， Foxp 2影响了PC多样化。引人注目的是，同时删除Foxp 1和Foxp 2会导致小脑的完全丧失。 大脑半球，在哺乳动物中重新进化，参与认知和语言功能。我们 长期目标是确定小脑神经元组装的分子和细胞机制。 电路我们推测Foxp 1和Foxp 2协同作用决定了PC组的分子特性 对小脑半球的形成和扩张至关重要。为了解决这个假设， 为了实现我们的目标，我们建议：1）使用单细胞转录组学和光片体积成像， 确定Foxp 1和Foxp 2如何调节小脑PC分化和形态发生，2）确定 突变体和对照小脑中Foxp 1和Foxp 2的全基因组结合谱。数据综合分析 从这些目标中产生的信息将揭示由Foxp 1的组合功能控制的转录网络 和Foxp 2基因在小脑发育中的作用。 拟议的培训计划是由博士袁浩詹姆斯李博士和博士贾斯汀科特尼在大学的赞助。 康涅狄格州健康中心培训计划的总体目标是为主要研究者Nagham Khouri法拉女士， 作为一名独立的科学家，为成功的职业生涯打下了坚实的基础。培训计划将帮助PI获得 经验：1）进行多组学实验和分析，2）负责任地进行研究，3） 与其他科学家合作，4）以书面和口头形式呈现数据，5）进行重要的 在遗传学、神经科学和发育生物学领域为科学界作出贡献。

PROJECT SUMMARY/ABSTRACT Mutations of FOXP1 and FOXP2, which encode forkhead box transcription factors, are associated with autism, mental retardation and language impairment. Functional studies in animal models have demonstrated combinatorial roles of FoxPs in the development of the CNS, particularly the forebrain. However, a clear understanding about their functional mechanisms is lacking. We recently discovered that molecularly heterogeneous populations of Purkinje cells (PCs) express different combinations of Foxp1, 2 and 4 in the mouse embryonic cerebellum. Through cerebellum-specific knockout experiments, we showed that the loss of Foxp1 or Foxp2 impacted PC diversification. Strikingly, deleting both Foxp1 and 2 resulted in a total loss of the cerebellar hemisphere, which has evolved de novo in mammals and is involved in cognitive and language functions. Our long-term goal is to determine the molecular and cellular mechanisms underlying the assembly of cerebellar circuitry. We hypothesize that Foxp1 and Foxp2 cooperatively specify the molecular identity of PC groups that are crucial for cerebellar hemisphere formation and expansion. To address this hypothesis and contribute to our goal, we propose to: 1) use single-cell transcriptomics and light-sheet volume imaging to ascertain how Foxp1 and Foxp2 regulate PC differentiation and morphogenesis of the cerebellum, 2) determine genome-wide binding profiles of Foxp1 and Foxp2 in mutant and control cerebella. Integrative analysis of data generated from these aims will unravel the transcription network governed by the combinatorial function of Foxp1 and Foxp2 in the developing cerebellum. The proposed training plan is sponsored by Dr. Yuanhao James Li and Dr. Justin Cotney at the University of Connecticut Health Center. The overall goal of the training plan is to provide the PI, Ms. Nagham Khouri Farah, with a solid foundation for a successful career as an independent scientist. The training plan will help the PI gain experiences: 1) to conduct multi-omics experiments and analyses, 2) to responsibly conduct research, 3) to collaborate with other scientists, 4) to present data in a written and oral format, 5) to make a significant contribution to the science community in the field of genetics, neuroscience and developmental biology.