果蝇突触粘附分子Neurexin调节突触生长的机制研究

Cognitive diseases like autism are global health problem. Exploring the pathogenetic mechanisms is current hot issue. Pedigree analysis found that mutations of human synaptic adhesion molecules are related to autism, but the detail mechanism is unknown. We previously showed the deletion of neurexin induces decreased synapse density in brain and less synaptic bouton in NMJ (neural muscular junction). Interestingly, after over-expressed neurexin in pre-synapse of NMJ, the number of satellite bouton is significantly increased. These results provide evidences that neurexin plays instructive role during synaptic growth. We further found that the level of p-Mad indicating BMP signaling activity is positively related to dosage of neurexin, the level of BMP receptor Thickveins (Tkv) is decreased in dnrx mutant and DNrx-mediated synaptic overgrowth is suppressed when wit of BMP signaling is deleted. These results suggest that Neurexin regulates synapse growth through BMP signaling probably. Based on our previous results, this research will study how Neurexin regulates synaptic growth through BMP signaling pathway using genetics, molecule biology methods, etc. This study could provide new mechanism about how the synaptic cell adhesion molecule Neurexin regulates synaptic growth and new clues for uncovering mechanisms for neuropathogenesis like autism.

孤独症等认知疾病是全球性公共健康问题。家系分析发现儿童孤独症与突触粘附分子Neurexin基因突变关联，但其致病机制不详。我们的前期研究表明：果蝇突触粘附分子DNRX（Neurexin）缺失后，脑和神经肌肉接头（NMJ）中的突触/神经突触扣结数目降低，而在NMJ突触前过表达DNRX导致突触过度生长，卫星突触扣结数量显著上升，表明DNRX对突触生长具有调控作用；预实验结果显示，DNRX的表达量与调控突触生长的关键信号通路BMP中Mad磷酸化水平紧密相关，DNRX缺失后BMP受体Tkv膜募集量下降而且过表达DNRX导致的突触过度生长被BMP信号受体wit缺失抑制，提示DNRX可能通过BMP信号调控突触的生长。本项目将以果蝇NMJ为模型，综合运用遗传学、分子生物学等手段，分析DNRX通过何种方式与BMP信号通路耦合进而阐明Neurexin调控突触生长的分子机制，为解析儿童孤独症的发病机理提供线索

Nrx是自闭症相关基因，我们以果蝇幼虫为模型，探索Nrx在神经系统发育与功能中的作用，为揭示疾病机制带来线索。我们制备了Nrx konck in 突变体，分析Nrx表达谱，发现Nrx不仅在神经肌肉接头表达，而且在感觉神经元中也有高表达，尤其是Class III和 Class IV。分析Nrx突变体幼虫行为（热，痛觉）后，我们发现Nrx突变体表现痛觉异常敏感行为，nrx作为跨膜突触黏附分子，与之相互作用的Nlgs是潜在的分子partner,我们分析了果蝇Nlg2,3,4后，Nlg4也存在痛觉异常行为。提示Nrx与Nlg4协同调节痛觉行为的可能性。自闭症儿童多伴随感觉极为敏感或者低于常人的感觉阈值，我们的研究为自闭症感觉异常提供了机制。