COUP-TFI基因在端脑腹侧发育中的功能及与神经系统疾病相关性研究

COUP-TFI基因突变与癫痫、智力障碍、自闭症等神经系统疾病休戚相关。COUP-TFI基因在小鼠端脑背侧的模式发生及皮层投射神经元（起源于端脑背侧）的分化过程中发挥关键作用，但它是否同样地参与端脑腹侧的模式发生及皮层中间神经元（起源于端脑腹侧）的分化尚不清楚。申请人发现COUP-TFI基因在小鼠早期胚胎端脑腹侧脑室区高表达；并成功培育端脑腹侧条件性COUP-TFI基因剔除小鼠（RXCre/+;COUP-TFIF/F）；观察到纹状体、杏仁复合体发育异常，皮层中间神经元数目减少。在此基础上，本项目拟研究COUP-TFI基因参与端脑腹侧的模式发生和皮层中间神经元分化的转录调控机制；研究COUP-TFI基因缺失导致的皮层神经元精细结构变化、突触传递的改变，以及行为异常。本项目对阐明端脑模式发生的调控机制，以及相关神经系统疾病的致病机理具有重要理论意义。

COUP-TFI gene mutations result in epilepsy, intellectual disorders, or autism spectrum disorders in human. The studies in mouse have demonstrated that COUP-TFI gene is one of the most important regulatory genes participating in the dorsal telencephalon patterning and the differentiation of cortical projection neurons. However, whether and how COUP-TFI gene is involved in the ventral telencephalon patterning and the differentiation of cortical interneuron hasn’t been clearly elucidated. We find that in embryonic ventral telencephalon, COUP-TFI gene is expressed highest in the ventricular zone, where reside neural stem cells. We have established the ventral telencephalon specific COUP-TFI gene conditional knockout (RXCre/+;COUP-TFIF/F) mouse successfully. In our preliminary study, we observed that the development of striatum and amygdala is abnormal, and cortical interneurons are significantly decreased in the COUP-TFI mutant mouse. We are planning to investigate the regulatory mechanism how COUP-TFI gene modulate the ventral telencephalon patterning and the differentiation of cortical interneuron, and what are the consequences on cortical neuron morphology, synapse formation and function, and mouse behaviors associated with the loss-of-function of COUP-TFI gene in the ventral telencephalon. Our study will benefits not only the understanding of the novel transcriptional networks regulating the telencephalon patterning, but also the understanding of the etiology of the neural diseases, such as intellectual disorders, epilepsy, autism spectrum disorders, or schizophrenia.