神经轴突导向分子Slit的功能及其分子作用机制研究进展

Current progress in functions of axon guidance molecule Slit and underlying molecular mechanism

神经轴突导向分子Slit是一种在进化上高度保守的分泌型糖蛋白,Slit对神经轴突导向、神经细胞迁移、神经细胞形态分化、肿瘤转移、血管生成、心脏形态发生等多种生命活动具有调节作用。Slit功能的实现主要是通过其LRR-2结构域与受体Roundabout(Robo)的Ig1结构域相结合而实现的,另外硫酸肝素蛋白多糖(heparan sulfate proteoglycans,HSPGs)、GTP酶激活蛋白(GTPase-activating proteins,GAPs)、酪氨酸激酶Abelson、Ca2+、MicroRNA-218和其它轴突导向分子等多种信号分子也参与了Slit功能的实现。slit基因受到Single-minded、Irx4和Midline等转录因子的调控,另外,转录后水平的选择性剪接使slit基因存在多种亚型。Slit导向机制的研究有助于揭示生物神经发育和再生过程中神经网络形成的内在分子基础,同时,也将为预防和治疗人类神经疾病、抑制癌细胞转移等提供理论参考。

The axon guidance molecule Slit is a secreted glucoprotein which is conserved during evolution.Slit has been implicated in regulating a variety of life activities,such as axon guidance,neuronal migration,neuronal morphological differentiation,tumor metas-tasis,angiogenesis and heart morphogenesis.Slit function mainly depends on the binding of its LRR-2 domain to the Ig1 domain of Roundabout （Robo） receptor,meanwhile Slit function is also mediated by a range of signaling molecules,including the heparan sul-fate proteoglycans （HSPGs）,GTPase-activating proteins （GAPs）,tyrosine kinase Abelson,calcium ions,MicroRNA-218 and other axon guidance molecules.Several transcription factors,including Single-minded,Irx and Midline,were shown to regulate slit expres-sion.In addition,multiple Slit isoforms exist as a consequence of alternative spliced transcripts.The research on guidance mechanism of Slit will facilitate the understanding of molecular mechanism underlying neural networks formation in the process of neural devel-opment and regeneration.Meanwhile,the studying of Slit guidance mechanism could promote the prevention and treatment of human neurological diseases and cancer metastasis.