Fmrp与lncRNA互作在神经元形态发生中的作用

Fragile X syndrome is caused by the functional loss of RNA binding protein, fragile x mental retardation protein (Fmrp), which leads to neurodevelopmental deficiency in the brain. How Fmrp regulate neuronal development is not well understood. Long non-coding RNA (lncRNA) plays an important role in neuronal development. How Fmrp control neuronal development through lncRNA has not been reported. Our previous study shows Fmrp deficiency leads to neuronal morphogenesis deficits of adult newborn neurons, and Fmrp binds to lncRNA Tug1 and regulates its expression, which suggested that Fmrp may control neuronal morphogenesis through regulating lncRNA. Based on previous findings, we aim to further investigate the molecular mechanisms of how Fmrp regulate the expression of lncRNA and the functional role of the interaction of Fmrp and lncRNA on the neuronal morphogenesis by using in vivo retro-virus delivery, “CLARITY” technology, RNA-immunprecipitation and qRT-PCR. The proposed study will help us to understand the etiology of fragile X syndrome, and provide us a new therapeutic theory of prevention and intervention for treating fragile X syndrome.

脆性X综合征是由RNA结合蛋白Fmrp表达缺失引起的，并最终导致大脑神经发育的缺陷。然而，Fmrp调控神经发育的分子机制仍然不清楚。长非编码RNA（lncRNA）在神经发育中起了重要作用。但是，Fmrp与lncRNA神经发育过程中相互作用的研究目前仍未见报道。我们前期的研究结果表明，Fmrp的缺失导致成体新生神经元形体发生的异常，并且Fmrp能够结合并调控lncRNA Tug1的表达。这一发现提示我们，Fmrp可能通过调控lncRNA的表达进而影响神经元形体发生。本项目将以此研究基础为切入点，运用在体逆转录病毒注射、“透明脑”、RNA-IP和qRT-PCR等实验手段进一步研究Fmrp通过调控lncRNA 的表达以及Fmrp与lncRNA互作在调控神经元形态发生中分子机制。此项目的研究结果将有助于我们了解脆性X综合征的发病机制，并为该疾病的预防和治疗提供新的理论依据。

脆性X染色体综合症(FXS)是常见的遗传性智力障碍疾病，由脆性X智力低下蛋白(FMRP)功能缺失所引起。长链非编码RNA (Long non-coding RNAs, LncRNAs)的表达异常可能是FXS的致病因素之一。然而，FMRP与LncRNAs的互作在神经发育的作用仍不清楚。RNA免疫共沉淀实验结果证明FMRP能够与TUG1互作并降低其稳定性。进一步通过体内外神经元标记， 发现TUG1能够与转录调控因子SnoN直接结合抑制其转录活性，特异地调控神经元轴突的发育。这一发现提示FMRP和lncRNAs的互作可能是脆性x综合征发病机制之一。