Investigating the role of CNTNAP2 gene in vocal learning in mutant songbirds

研究 CNTNAP2 基因在突变鸣禽声音学习中的作用

• 批准号: 8413323
• 负责人: CARLOS LOIS
• 金额: $ 24.91万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-13 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8413323
• 关键词: Acute; Adolescent; Affect; Anatomy; Animal Model; Animals; Area; Autistic Disorder; Behavior; Behavioral; Birds; Boxing; Brain; Cell Nucleus; Communication; Communication impairment; Development; Disease; Dissection; Down-Regulation; Engineering; Exhibits; Genes; Genetic; Hearing; Human; Impairment; Laboratories; Language; Language Development; Lead; Learning; Lentivirus Vector; Link; Maps; Mediating; Memory; Messenger RNA; Methods; Modeling; Modification; Molecular; Mutation; Neurodevelopmental Disorder; Pathway interactions; Patients; Performance; Play; Predisposition; Production; Property; Proteins; RNA Interference; Research; Research Personnel; Role; Series; Signal Transduction; Songbirds; Speech; System; Transgenic Organisms; autism spectrum disorder; base; communication behavior; contactin; critical period; developmental disease; forkhead protein; genetic manipulation; mutant; prevent; social; specific language impairment; tool; vocal learning; vocalization; zebra finch

DESCRIPTION (provided by applicant): Communication impairments are some of the most debilitating consequences of a number of neurodevelopmental disorders, including autism spectrum disorders (ASD). It is thought that the communication impairments associated with neurodevelopmental disorders may be due to the perturbed assembly of brain areas involved in vocal communication. In recent years a number of genes, including the transcription factor FoxP2 and its target CNTNAP2, have been linked to language specific impairments and to ASD in humans, suggesting that they could play a direct role in speech and language acquisition. However, the lack of adequate animal models to specifically study vocal learning and communication has prevented the dissection of the genetic components involved in communication behaviors. Songbirds are currently the best animal model to study vocal communication because song learning in these animals shares critical features with speech acquisition in humans. Moreover, songbirds have a dedicated brain circuit that is required for the learning and production of vocal signals. Finally, both Foxp2 and CNTNAP2 are expressed in the song system suggesting that speech acquisition in humans and song learning in songbirds involves similar molecular pathways. Thus, songbirds could be an excellent model to study the genetic basis of communication-related aspects of neurodevelopmental disorders, as they represent the ideal system to study how genes orchestrate the assembly of a brain circuit dedicated to vocal learning and production. Our laboratory has developed new methods for the genetic modification of songbirds that will enable us and other researchers to generate genetic animal models for vocal communication disorders. In this proposal we describe a plan to generate genetically-engineered songbirds deficient in CNTNAP2, which will open a new avenue for investigating the role of genes on the assembly and function of the brain circuits involved in vocal communication. This approach should lead to a better understanding on how mutations in this and other genes result in communication deficits such as the ones observed in patients with ASD and other neurodevelopmental disorders. PUBLIC HEALTH RELEVANCE: Impaired vocal communication is one of the most debilitating deficits observed in a number of diseases due to abnormal brain development, such as autism. Recent studies have identified several genes associated with autism and other disorders that impair communication. Songbirds are currently the best animal model to study vocal communication because song learning in these animals shares several critical features with speech acquisition in humans. We propose to generate a genetically-engineered songbird in which one of these autism-related genes is disrupted to investigate how genes orchestrate the assembly of the brain circuits involved in vocal communication.

描述（由申请人提供）：沟通障碍是一些神经发育障碍，包括自闭症谱系障碍（ASD）的最衰弱的后果。据认为，与神经发育障碍相关的沟通障碍可能是由于参与语音沟通的大脑区域的干扰组装。近年来，包括转录因子FoxP2及其靶基因CNTNAP 2在内的许多基因与人类语言特异性损伤和ASD有关，这表明它们可能在言语和语言习得中发挥直接作用。然而，由于缺乏足够的动物模型来专门研究发声学习和交流，阻碍了对参与交流行为的遗传成分的解剖。鸣禽是目前研究声音交流的最佳动物模型，因为这些动物的歌曲学习与人类的语音习得具有关键特征。此外，鸣禽有一个专门的大脑回路，这是学习和产生声音信号所必需的。最后，Foxp2和CNTNAP 2都在鸣唱系统中表达，这表明人类的语音习得和鸣禽的鸣唱学习涉及类似的分子途径。因此，鸣禽可能是一个很好的模型来研究神经发育障碍的沟通相关方面的遗传基础，因为它们代表了研究基因如何协调专门用于声音学习和生产的大脑回路组装的理想系统。我们的实验室已经开发出了对鸣禽进行基因改造的新方法，这将使我们和其他研究人员能够为声音交流障碍建立遗传动物模型。在这项提案中，我们描述了一个计划，以产生基因工程的鸣禽CNTNAP 2缺陷，这将打开一个新的途径，调查基因的作用，对组装和功能的大脑回路参与声乐交流。这种方法应该能更好地理解这种基因和其他基因的突变如何导致沟通缺陷，例如在ASD和其他神经发育障碍患者中观察到的沟通缺陷。 公共卫生相关性：声音交流障碍是在许多疾病中观察到的最令人衰弱的缺陷之一，这些疾病是由于大脑发育异常，如自闭症。最近的研究已经确定了几个与自闭症和其他损害交流的疾病有关的基因。鸣禽是目前研究声音交流的最佳动物模型，因为这些动物的歌曲学习与人类的语音习得有几个关键特征。我们建议产生一种基因工程鸣禽，其中这些自闭症相关基因之一被破坏，以研究基因如何协调参与声音交流的大脑回路的组装。