转录因子COUP-TFI和COUP-TFII调控大脑皮质中间神经元发生发育的分子机制

The mammalian neocortex contains two main neuron subpopulations, the excitatory glutamatergic projection neurons and the inhibitory GABAergic interneurons. It is being recognized that cortical interneurons through their maintenance of the excitatory/inhibitory balance in the cerebrum are central to the normal function of the nervous system. Moreover, recent studies in mouse models and humans have indicated that interneuron dysfunction is associated with neurological and psychiatric diseases such as epilepsy, schizophrenia and autism。The diversity of cortical interneurons derived from concise and complex regulation by transcription factors during embryonic development. The transcription factor Coup-TF I and Coup-TFII are nuclear receptors belonging to the superfamily of the steroid/thyroid hormone receptors,and have been involved in regulation of neural development. However, the regulation and molecular mechanism underlying Coup-TFI and Coup-TF II in the regulation of cortical interneurons development remains totally unknown. In the present project, the regulation of Coup-TFI and Coup-TFII in cortical interneuron development and underlying molecular mechanisms will be investigated by means of immunostaining, cellular and molecular biology methods, confocal scanning, patch clamp and Time-lapse video recording. It will provide experimental data for employing stem cells derived from human to ameliorate neurological disorders associated with cortical interneuron dysfunction.

大脑皮质由兴奋性投射神经元和抑制性中间神经元组成，中间神经元对投射神经元活动的精细调控是大脑皮质发挥正常生理功能的基础。研究发现，中间神经元的发生发育异常与神经系统疾病密切相关，如癫痫、自闭症和精神分裂症等。大脑皮质中间神经元的多样性起源于胚胎发育时期各种转录因子对神经干细胞精密和复杂的调控。转录因子Coup TFI/II属于孤核受体家族成员，在神经系统发育中调控神经发生、神经干细胞分化和迁移以及轴突生长，但它们在大脑皮质中间神经元发生发育过程中的调控及可能分子机制却不甚清楚。本课题将利用条件性基因敲除技术，结合免疫组织化学、细胞和分子生物学以及电生理等方法，使用激光共聚焦和活细胞成像手段，研究转录因子Coup-TFI和Coup-TFII对大脑皮质中间神经元发生发育的调控作用及分子机制。这一研究将为利用神经干细胞治疗神经系统疾病提供实验依据。

兴奋性和抑制性的动态平衡对大脑皮质发挥正常功能是至关重要的。大脑皮质中间神经元的多样性起源于胚胎发育时期各种基因和转录因子对神经干细胞精密和复杂的调控作用。本项目研究了转录因子Coup-TFI和Coup-TFII在大脑皮质中间神经元发生发育过程中的调控作用。我们发现条件性敲除Coup-TFI和Coup-TFII，脑室下层正在分裂的神经干细胞数量增加，转录因子Coup-TFI通过上调SHH和FGF信号促进大脑皮质神经干细胞的分化。同时，我们发现转录因子Sp9在MGE起源的大脑皮层中间神经元的发育过程中具有中心转录作用，转录因子Sp8和Sp9协同调控MGE起源的大脑皮质中间神经元和CGE起源的大脑皮质中间神经元迁移。嗅球是端脑皮质的一部分，我们发现转录因子Dlx1/2和PROK2/PROKR2信号传导通路调控嗅球中间神经元的发育。此外，我们还发现转录因子Zfhx3在纹状体胚胎后期产生的D1中间大小棘状神经元的分化过程中有着必不可少的作用。相关研究成果以SCI论文的形式发表在 Front Molecular Neuroscience、Cerebral Cortex、J Comparative Neurology、Experimental Neurology国际学术期刊上。