果蝇细胞表面受体Dscam1在轴突分支形成中的功能与调控机制研究

The Drosophila Dscam1 gene can generate thousands of isoforms via alternative splicing and the isoform diversity is important for neuronal self-recognition and self-avoidance. However, the molecular mechanism of Dscam1 signaling regulation, as well as the cellular mechanism underlying Dscam1-mediated neuronal responses remains unclear. We previously reported that Dscam1 signaling strength controls growth cone sprouting and axon collateral formation. Recently, we found that the SH2/SH3 adaptor protein, Dock, negatively regulates Dscam1 activity, contrary to its positive role in axon guidance and dendrite growth at embryonic stages as previously reported. We also identified in the C-terminus of Dscam1 a tyrosine residue whose phosphorylation is critical for controlling Dscam1 activity. We plan to further investigate the molecular mechanisms controlling Dscam1 activity, i.e. the influence of tyrosine phosphorylation on Dscam1-Dock binding, as well as identifying the key kinase(s) that phosphorylates Dscam1 during axon branching. Using live imaging, we will also explore the cellular mechanism of axon branching underlying Dscam1 signaling. This study will provide the insight into molecular mechanisms of neuronal target specificity, and the new therapeutic strategy to Down Syndrome.

具有高度分子多样性的果蝇唐氏综合症细胞粘附因子（Dscam1）在神经元自我识别与自我回避中发挥重要的功能。但细胞膜内调控Dscam1信号开启的分子作用机制以及Dscam1最终所介导的细胞生物学过程仍不清楚。我们以前的工作显示Dscam1缺失或过激活均引起机械感觉神经元轴突分支缺陷。我们最近的研究发现在轴突分支中与Dscam1 相结合的SH3/SH2接头蛋白Dock对Dscam1信号行使负调控功能，而非以前认为的正调控。我们还鉴定出Dscam1胞内区具有重要调节功能的酪氨酸磷酸化修饰位点。本项目将进一步研究调节Dscam1功能的分子作用机制，如发现酪氨酸磷酸化修饰对Dscam1与Dock结合的调节作用，以及从发现Dscam1的磷酸激酶入手研究开启Dscam1磷酸化修饰的分子机理。此外，我们将运用实时成像技术探索Dscam1所介导的细胞生物学效应。该研究可能为唐氏综合症的致病机理提供理论依据。