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

描述（由申请人提供）：沟通障碍是包括自闭症谱系障碍（ASD）在内的许多神经发育障碍的一些最衰弱的后果。人们认为，与神经发育障碍相关的交流障碍可能是由于参与声音交流的大脑区域的组装受到干扰。近年来，包括转录因子FoxP2及其靶基因CNTNAP2在内的许多基因与人类的语言特异性障碍和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，缺乏足够的动物模型来专门研究声乐学习和交流，这阻碍了对交流行为中涉及的遗传成分的解剖。鸣禽是目前研究声音交流的最佳动物模型，因为这些动物的鸣叫学习与人类的语言习得具有共同的关键特征。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CNTNAP2都在鸣叫系统中表达，这表明人类的语言习得和鸣禽的鸣叫学习涉及相似的分子途径。因此，鸣禽可能是研究神经发育障碍中与交流相关方面的遗传基础的绝佳模型，因为它们代表了研究基因如何协调致力于声音学习和产生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产生声音交流障碍的遗传动物模型。在这篇论文中，我们描述了一种产生CNTNAP2基因缺陷的基因工程鸣禽的计划，这将为研究基因在参与声音交流的大脑回路的组装和功能中的作用开辟一条新的途径。这种方法应该能让我们更好地理解这种基因和其他基因的突变是如何导致交流缺陷的，比如在ASD和其他神经发育障碍患者中观察到的缺陷。

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.