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 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.

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。

临床研究发现，COUP-TFI基因突变与智力障碍症和孤独症等的发生休戚相关。COUP-TFI基因在小鼠端脑背侧模式发生及背侧端脑起源皮层兴奋性投射神经元的分化过程中发挥关键作用；然而，COUP-TFI基因是否参与腹侧端脑起源皮层抑制性中间神经元的分化，及其功能异常引起神经系统发育相关疾病的机理尚不清楚。本项目研究发现，COUP-TFI基因在小鼠早期胚胎腹侧端脑脑室区高表达；并成功培育腹侧端脑条件性COUP-TFI基因敲除RXCre/+;COUP-TFIF/F小鼠模型和携带孤独症患者COUP-TFI基因Arg112Lys突变的COUP-TFIm/+小鼠模型；免疫荧光染色结果显示：RXCre/+;COUP-TFIF/F纯合突变小鼠皮层中间神经元数目降低，而杂合COUP-TFIm/+点突变小鼠皮层中间神经元数目增加；电生理记录数据揭示：RXCre/+;COUP-TFIF/F纯合突变小鼠和杂合COUP-TFIm/+点突变小鼠均表现出皮层兴奋性/抑制性失衡；成年杂合COUP-TFIm/+点突变小鼠表现出孤独症相关的社会行为和重复行为异常；RNA-seq和ChIP-seq相结合的系统生物信息分析揭示：介导早期腹侧端脑模式发生的Sonic hedgehog (SHH)信号通路异常激活；GABA受体拮抗剂—银杏内酯A能部分缓解杂合COUP-TFIm/+点突变小鼠的社会行为异常。本项目工作证实，SHH信号通路相关的腹侧端脑起源皮层抑制性中间神经元发育异常，引起皮层兴奋性/抑制性失衡，可能是导致神经系统发育相关疾病尤其是孤独症的病因之一；本项目的实施与完成为探讨神经系统发育相关疾病如孤独症、智力障碍症等的致病机理以及疾病的临床治疗手段，提供了新的思路。