胶质细胞泛素连接酶dSmurf调控蘑菇体神经发育的机制研究

Neurodevelopment and degeneration mainly rely on neuronal function and passive support from glial cells. Recently, abundant evidence has elucidated the role of glia in neurodevelopment, circuit, and synaptic transmission, raising attention to the importance of glia in all aspects of neuronal function. Previous studies suggest that ubiquitin-mediated protein degradation play important roles in glial development, but its role in glia-neuron interaction, neurodevelopment, and diseases pertaining neurodevelopment remain unclear. Our study aims to explore the mechanism of glia-derived ubiquitin E3 ligase dSmurf in regulating Drosophila mushroom body development and function. Our previous results suggest an altered morphology and number of mushroom body Kenyon (KC) cells upon overexpressing dSmurf in glia, particularly alpha and beta KC cells. Based on these data, we will investigate the mechanism of glia-derived dSmurf regulating KC neuroblast proliferation. In addition, we will also investigate the possibility of glial dSmurf affecting the temporal identity of different KC cells. We will also determine the developmental pathways that glial dSmurf functions in to lead to these changes, identify the protein-protein interaction between dSmurf and Fused, and elucidate the mechanism of dSmurf-mediated Fu ubiquitination. In-toto, these results will help to understand how glial dSmurf regulates neurodevelopment using mushroom body as a model system, and provide possible therapeutic solution for treating neurodevelopmental disorders.

神经发育成熟及退化仰赖神经元功能与胶质细胞提供的营养支持。近年来，研究阐明胶质细胞主动调节神经发育，使得它的功能受到重视。已知介导蛋白质稳定性的泛素化修饰在胶质细胞发育中起关键作用，然而其如何调控胶质细胞与神经元的相互作用、神经发育及相关疾病发生等问题仍不甚清楚，有待突破。本项目拟开展胶质细胞泛素连接酶dSmurf调控神经发育的机制研究，以果蝇大脑学习记忆中枢蘑菇体为模型，深入探讨：1）胶质细胞dSmurf调控蘑菇体神经前体细胞增殖的详细机制，揭示胶质细胞泛素化修饰为神经前体细胞增殖微环境的重要元件，2）胶质细胞dSmurf调控蘑菇体神经元分化次序的机制，3）鉴定dSmurf作用的发育通路，明确dSmurf与Hedgehog通路成员Fused的结合作用，以及介导Fu泛素化的机制。通过这些研究，将促进理解胶质细胞调控神经发育的详细机理，为神经发育疾病提供预防诊疗的可能手段与新型思路。

神经发育成熟及退化仰赖神经元功能与胶质细胞提供的营养支持。近年来，研究阐明胶质.细胞主动调节神经发育，使得它的功能受到重视。已知介导蛋白质稳定性的泛素化修饰在胶质.细胞发育中起关键作用，然而其如何调控胶质细胞与神经元的相互作用、神经发育及相关疾病.发生等问题仍不甚清楚，有待突破。本项目拟开展胶质细胞泛素连接酶dSmurf调控神经发育的.机制研究，以果蝇大脑学习记忆中枢蘑菇体为模型，发现胶质细胞dSmurf调控蘑菇体神经前体.细胞增殖的详细机制。我们揭示了dSmurf作用的发育通路，明确dSmurf与Hedgehog通路成员.Patched的结合作用。我们也阐明了dSmurf调控FasII稳定性从而影响细胞粘附的机制，明确胶.质细胞泛素化修饰在神经前体细胞增殖微环境的重要性。