以模式动物果蝇解析精神分裂症易感基因Vein(Neuregulin)的功能及相关病理机制

Schizophrenia is a mental disorder with multiplex etiology and multiform clinical features. By human genetic studies we have identified a lot of candidate genes/sites for schizophrenia, and the next step it is to find out the function of single gene and multiple genes, and the underlying pathological mechanisms. We plan to investigate the function and the modulation mechanisms of some schizophrenia susceptibility genes on Drosophila Model, from molecular and cellular level to behavior effects. First, we will discuss the strategies to use Drosophila to study psychiatric disorders, like schizophrenia. Then we will focus on some important relevant genes, including Vein/EGFR, dNR1/2, trh, and dys. We have some transgenic lines, such as inhibiting the dNR1 or dNR2 by dsRNA, and over expression and mutants of Vein and EGFR et al. Our preliminary results show that reduced expression of dNR1 or dNR2 significantly leads to deficits in social behaviors, like altered male mating orientation. We propose that suppression of NMDA receptor expression may alter the pheromone neural circuits in the fly brain. Meanwhile, we notice that Vein/EGFR signaling maintains glia survival during axon guidance, especially for ventral nervous cord (VNC) longitudinal axon trajectory, which links the sensory and motor systems, including pheromone signaling. Vein and EGFR mutants also alter the male mating preference. So our research mainly includes the underlying cellular mechanisms of altered social behaviors induced by suppression of Vein/EGFR Signaling, and the possible functional interaction with NMDA receptor subunits. We also plan to find out the function of some new genes (such as trh and dys), which could be susceptible to schizophrenia, by using these well-defined approaches in our lab.

精神分裂症发病原因复杂，临床症状多样。虽然已找到多个易感基因，但是对于许多单基因、多基因综合功能和病理机制还不清楚。我们利用相对低等的模式动物果蝇研究精神分裂症相关基因功能和调控机制。首先论述利用果蝇研究精神疾病基因功能的可行性，然后选择性研究一些重要易感同源基因如Vein/EGFR、dNR1及新发现的如 dys、trh等。通过Vein和dNR1/2的相关突变体等的初步实验表明抑制Vein和dNR1/2功能均能影响果蝇社交行为，比如雄性求偶行为异常，我们猜测该行为可能通过影响信息素信号传输的神经网络。果蝇Vein/EGFR信号调控胶质细胞-神经元相互作用，是腹神经束（VNC）等轴突发育的关键调节因子。我们的研究内容主要为Vein/EGFR对动物行为影响的细胞调控机制，包括找出一些关键的分子，及Vein与dNR1/2可能的相互关联作用。我们同时通过类似手段研究其他可能的易感基因的功能等。

我们利用vein(vn)、dNR1/2等突变体进行了多种行为筛选，并且尝试了部分机制研究。目前已获得一些重要的数据，部分研究结果准备整理发表。我们的研究显示vn突变体（vnγ3和vnRNAi)影响果蝇交配行为和节律活动等。为进一步研究其机制，我们根据行为特征寻找其可能作用的神经元。通过形态学上的检测，我们观察到vn影响一类重要节律神经元sLNvs（small ventral lateral neurons）神经元轴突形成，包括轴突分枝数目降低以及PDF（pigment-dispersing factor）在轴突含量降低，并且直接导致PDF节律性释放紊乱。我们通过RNA干扰分别降低dNR1和dNR2（dNR1-RNAi和dNR2-RNAi）的表达水平。实验表明NMDA受体亚基表达被抑制后影响了果蝇的交配行为，和vn突变体结果类似，但是没有发现对节律活动有影响。我们的实验结果展示了vn和dNR1/2虽然同属精神分裂症易感基因，但其对动物行为影响却有所不同。同时降低NMDA受体和vn表达水平与并未加深对交配行为的影响，提示NMDA受体与vn可能通过同一信号途径影响该社交行为。抑制vn的表达降低果蝇EB（Ellipsoid body）区域的dNR2含量，提示vn可能通过调控NMDA受体的表达影响果蝇交配活动，虽然抑制EB区域抑制vn表达并不影响果蝇社交行为。提示，vn作为一类神经分泌小分子蛋白，周围神经元可能通过分泌vn间接影响EB区域NMDA受体亚基表达。 其具体作用途径和机制目前还在进一步研究中，我们初步研究提示可能与果蝇EB区域的NMDA受体有关。