FMRP靶基因FYN在脆性X综合征中调控突触发育的机制研究

脆性X综合征（FXS）重要的致病原因是FMRP缺失引发的PIKE-L/PI3K通路过度激活，进而引起突触发育异常，最终导致发育迟缓和认知障碍，但机制不明。我们鉴定出两个新的FMRP靶基因FYN和NETRIN1，报道显示二者都参与调控PIKE-L/PI3K通路，NETRIN1调控FYN活性。我们发现FMRP抑制FYN和NETRIN1翻译，FXS中FYN调控PIKE-L活性，我们提出假设：在FXS中，FMRP缺失一方面导致FYN表达过量直接增强其激酶活性，另一方面导致NETRIN1表达过量间接促使FYN活性增强，两方面协同引起PIKE-L/PI3K通路过度激活，最终引起突触发育异常。本项目拟通过果蝇突触形态、传递和学习记忆，从表达水平和激酶活性层面证明FYN是PIKE-L/PI3K通路关键分子，发现FYN和NETRIN1协同调控新模式，解析FXS中PIKE-L/PI3K通路过度激活的机制。

Fragile X Syndrome (FXS) is the most common form of inherited intellectual disability and the leading cause for autism spectrum disorder. It is caused by the absence of fragile X mental retardation protein (FMRP).Loss of FMRP results in excessive protein synthesis and exaggeration of PIKE-L/PI3K pathway, which in turn alters neural development and function during the synapse and dendritic spine development. However, the underlying mechanisms are not clear. It is of great importance to identify FMRP targets and study how PIKE-L/PI3K signaling is upregulated. We recently identified two new FMRP targets, FYN and NETRIN1. Others found that PIKE-L/PI3K signaling was activated by FYN and NETRIN1. Increased level of NETRIN1 can enhance the kinase activity of FYN. We found that FYN and NETRIN1 were translationally repressed by FMRP, and FYN could activate PIKE-L in FXS. We propose the synergic effect of excessive FYN protein caused by loss of repression of FMRP and hyperactive kinase of FYN induced by NETRIN1 contributes to the exaggeration of PIKE-L/PI3K signaling in FXS. In this study, FXS drosophila model will be utilized to reveal the synergic effect of FYN and NETRIN1 underlying mechanism of exaggerated PIKE-L/PI3K pathway, which altered the synaptic morphology, transmission and learning and memory. This study uncovers a role for elevated expression and activity of FYN, as a crucial contributor to PIKE-L/PI3K causing synaptic and memory impairments in FXS, and a new regulation for synergic effect of FYN and NETRIN1 contributing to exaggerated PIKE-L/PI3K signaling. This study may deepen our understanding of FXS pathogenesis and offer potential strategies to normalize the hyperactivity of PIKE-L/PI3K pathway.