【作者】 张哲；

【导师】 赵春杰；

【作者基本信息】 东南大学 ， 基础医学， 2022， 硕士

【摘要】 纹状体位于腹侧端脑,由外侧神经节隆起分化产生,是基底神经节的主要输入-输出部位。纹状体作为基底神经节的主要信息处理中心,在接收到不同脑区的输入信息后,经过信息的整合,将指令通过直接输出途径和间接输出途径传出至基底神经节的其他结构,从而规范运动行为。纹状体神经元包括～95%的纹状体投射神经元和～5%的纹状体中间神经元。纹状体投射神经元参与调控纹状体输出途径,包括两种纹状体神经元亚型,直接途径纹状体投射神经元和间接途径纹状体投射神经元。直接途径纹状体投射神经元促进运动功能,间接途径纹状体投射神经元抑制运动功能。这两种纹状体投射神经元的发育异常,导致两条纹状体输出途径之间的失衡,进而引发纹状体相关的运动障碍。对纹状体投射神经元其发育的深入研究将为相关疾病的发病机制及治疗策略提供重要线索。FOXG1综合征是由于FOXG1基因突变导致,FOXG1综合征患者的临床表型包括认知功能障碍、精神异常以及肌张力障碍、舞蹈症、手足徐动症等混合运动功能障碍,提示FOXG1可能与纹状体投射神经元发育相关。本研究通过在纹状体前体细胞和有丝分裂后神经元中特异性敲除Foxg1,探究FOXG1在纹状体投射神经元亚型特化过程中的调控作用。我们发现在纹状体前体细胞中特异性敲除Foxg1,E18.5天纹状体投射神经元总体数量显著减少,两种纹状体投射神经元亚型的数量也明显减少;进一步研究发现,神经元的亚型特化进程受到阻滞,无法获得正常的直接途径纹状体投射神经元和间接途径纹状体投射神经元命运。在有丝分裂后直接途径纹状体投射神经元中特异性敲除Foxg1,发现直接途径纹状体投射神经元异常表达间接途径纹状体投射神经元的特异性分子标记物,证明FOXG1抑制间接途径纹状体投射神经元的特化,促进直接途径纹状体投射神经元的特化。我们的研究表明Foxg1的缺失导致纹状体投射神经元亚型特化异常,这可能是造成FOXG1综合征运动功能障碍的原因之一。本研究有助于阐明纹状体投射神经元亚型特化的发育调控机制,并为深入理解FOXG1综合征的发病机制奠定了基础。更多还原

【Abstract】 The striatum which is differentiated from the lateral ganglion eminence is located in the ventral telencephalon,and is the main input-output part of the basal ganglia.The striatum is the main information processing center of the basal ganglia.After receiving input information from different telencephalon parts and integrating information,the striatum transmits instructions to other parts of basal ganglia through direct and indirect output pathways,so as to regulate motor behavior.Striatal neurons include ～95% spiny projection neurons and ～5% striatal intermediate neurons.Spiny projection neurons are involved in the regulation of striatal output pathway and include two subtypes,direct pathway spiny projection neurons and indirect pathway spiny projection neurons.Direct pathway spiny projection neurons promote motor function,indirect pathway spiny projection neurons inhibit motor function.Abnormal development of these two subtypes of spiny projection neurons leads to an imbalance between the two striatal output pathways,which leads to striatal related dyskinesia.The research of spiny projection neurons’ development will provide important clues for the pathogenesis and treatment strategies of related diseases.FOXG1 syndrome is caused by the mutations of FOXG1 gene.Patients exhibit cognitive dysfunction and psychiatric disorders,and suffer from mixed dyskinesia such as dystonia,chorea and athetosis,suggesting that FOXG1 may be related to the development of spiny projection neurons.In this study,Foxg1 is specifically deleted in the striatal progenitors and postmitotic neurons to explore the role of FOXG1 in the subtype specification of spiny projection neurons.We find that the total number of spiny projection neurons and the two subtypes of spiny projection neurons are significantly reduced at E18.5 days after Foxg1 deletion in the striatal progenitors.Further studies show that the specification of neurons subtype is blocked,and normal fate of direct and indirect pathway spiny projection neurons could not be obtained.In the postmitotic direct pathway spiny projection neurons which are specifically deleted Foxg1,we find that direct pathway spiny projection neurons abnormally express specific molecular markers which normally express in indirect pathway spiny projection neurons.These results demonstrate that FOXG1 inhibits the specification of indirect pathway spiny projection neurons and promotes the specification of direct pathway spiny projection neurons.Our study suggests that the deletion of Foxg1 leads to abnormal subtype specification of spiny projection neurons,which may be one of the causes of dyskinesia in FOXG1 syndrome.This study is useful to elucidate the developmental regulatory mechanisms underlying the development of spiny projection neurons and lays a foundation for further understanding the pathogenesis of FOXG1 syndrome.更多还原