果蝇细胞表面受体分子Dscam1胞内区新功能与调控机制的研究

Drosophila Dscam1 （Down Syndrome Cell Adhesion Molecule）is critical for many process involved in neuronal wiring, such as neuronal self-recognition, self-avoidance and target selection. However, the regulatory mechanism of Dscam1 signaling is still poorly understood. We previously found that Dscam1 molecular diversity plays an important role in axonal branching. Recently, we unexpectedly found that overexpression of Dscam1 in the primordium of scutellum interferes with Notch signaling, and genetically interacts with the component of Notch pathway, ϒ-secretase Presenilin (Psn). Engineered Dscam1 in which the C-terminus is fused with a transcriptional activation domain , strongly drives the expression of the reporter gene in central nervous system, indicating that the intracellular domain (ICD) of Dscam1 is cleaved by a proteinase, and hence released from membrane. Moreover, loss of Psn phenocopies gain of Dscam1 signaling in terms of axonal branching. These results collectively suggest that the cleavage of Dscam1 transmembrane domain by Psn may play a regulatory role in Dscam1 signaling. We plan to further investigate the molecular mechanisms underlying regulation of Dscam1 activity, i.e. Dscam1 ICD cleavage by Psn. We will also explore novel function of the cleaved Dscam1 ICD in axon and dendrite morphogenesis.

果蝇唐氏综合症细胞粘附因子Dscam1在神经环路形成中发挥着重要的功能，包括神经元自我识别、自我回避和靶细胞识别等。但调控Dscam1信号的分子作用机制仍不清楚。我们最近意外发现过表达Dscam1会干扰Notch信号转导途径，与Notch途径的成员基因ϒ-分泌酶Presenilin (Psn) 有遗传学互作。本体水平改造的具有转录激活活性的Dscam1能够在神经系统较强地激活报告基因表达，提示Dscam1 胞内区被蛋白酶切割后从细胞膜释放出来。此外，缺失Psn与Dscam1过度激活在机械感觉神经元轴突形态上的表型类似。基于以上结果，我们推测Psn可能通过切割Dscam1跨膜区释放出胞内区来对Dscam1信号转导途径进行调节。本项目将进一步研究发现ϒ-分泌酶Psn调节Dscam1功能的机理，并从Dscam1的胞内区酶切后释放的片段的功能入手，发现Dscam1调节轴突和树突形态发育的新机制。

果蝇神经元表面受体唐氏综合症细胞粘附因子(Down Syndrome Cell Adhesion Molecule, Dscam1) 在神经系统环路形成中发挥着广泛且重要的功能。Dscam1胞外区分子多样性为神经元自我识别与自我回避中提供了分子基础，但细胞膜内Dscam1四种剪接异构体的功能及差异仍不清楚。此外，Dscam 家族成员虽然在功能上有一定程度的冗余，但功能的冗余是否通过激活共同的下游信号转导途径来实现也未得到证实。本研究旨在研究Dscam1胞内区分子多样性在神经环路形成中的功能以及Dscam1家族成员胞内区功能的差异。.本研究首先建立适合改造 Dscam1 胞内区的遗传学系统，通过该系统构建一系列适合研究Dscam1胞内区剪接异构体表达模式及功能差异的各种遗传学工具。利用这些遗传学工具我们系统研究了 Dscam1 胞内区剪接异构体在中枢神经系统的表达模式和在神经环路形成中的功能差异。此外，我们还系统研究了 Dscam 家族成员之间胞内区在神经环路形成中的功能差异。.总之，本研究的发现为进一步深入理解Dscam1在神经环路形成中的功能调控机制以及 Dscam 家族成员功能的趋同和趋异进化提供了实验依据。