Functional dissection of mammalian vocal communication

 描述（由申请人提供）：语音通信的神经基础仍然是未知的。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声音交流中重要的分子信号通路。编码FOXP 2的基因突变先前已在患有言语和语言障碍的个体中被鉴定。此外，FOXP 2转录调节许多涉及神经发育障碍如自闭症和精神分裂症的基因。我们的初步研究表明，FOXP 2在小脑的表达是重要的正常发声和运动功能。此外，我们还发现了FOXP 2的一个保守的翻译后修饰位点，它对基因表达调控和运动功能非常重要。基于这些数据，驱动这一提议的中心假设是FOXP 2的翻译后修饰对于调节发声和运动功能至关重要。我们 提出通过以下四个特定目的操纵小鼠小脑中Foxp 2的表达来鉴定FOXP 2的转录后修饰对小脑特异性基因表达和运动功能的作用：1）确定发育中小脑中Foxp 2的表达是否对发声和基因表达重要; 2）评估Foxp 2的翻译后修饰对发声的作用; 3）确定Foxp 2的翻译后修饰对基因表达的作用;和4）评估Foxp 2的翻译后修饰对运动功能的作用。总之，这些目标将确定Foxp 2在小脑中调控的转录程序，以及Foxp 2基因调控如何与发声和其他运动相关行为相关。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个人与沟通障碍，小脑为基础的运动障碍，自闭症，其中涉及破坏小脑功能。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): The neural underpinnings of vocal communication remain mostly unknown. The long-term goal of our laboratory is to elucidate the molecular signaling pathways important in vocal communication that are disrupted in neurodevelopmental disorders. Mutations in the gene encoding FOXP2 have previously been identified in individuals with speech and language disorders. In addition, FOXP2 transcriptionally regulates many genes involved in neurodevelopmental disorders such as autism and schizophrenia. Our preliminary studies have shown that expression of FOXP2 in the cerebellum is important for normal vocalizations and motor function. Moreover, we have uncovered a conserved site of post-translational modification of FOXP2 that it is important for gene expression regulation and motor function. Based on these data, the central hypothesis driving this proposal is that post-translational modification of FOXP2 is critical for regulating vocalizations and motor function. We propose to identify the role of post-transcriptional modification of FOXP2 on cerebellar-specific gene expression and motor function by manipulating Foxp2 expression in the mouse cerebellum through four specific aims: 1) Determine whether Foxp2 expression in the developing cerebellum is important for vocalizations and gene expression; 2) Assess the role of post-translational modification of Foxp2 on vocalizations; 3) Determine the role of post-translational modification of Foxp2 on gene expression; and 4) Assess the role of post-translational modification of Foxp2 on motor function. Together, these aims will determine the transcriptional program regulated by Foxp2 in the cerebellum and how Foxp2 gene regulation may be related to vocalizations and other motor-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 communication disorders, cerebellar based motor disorders, and autism, which involves disrupted cerebellar function. These data will also provide insight into the basic molecular mechanisms governing normal brain development.