Deciphering the mRNP Code for Successful Glia to Neuron Reprogramming

破译 mRNP 代码以实现神经胶质细胞成功重编程

• 批准号: 427451793
• 负责人: Professor Dr. Michael Kiebler
• 金额: --
• 依托单位: Lehrstuhl Anatomie III - Zellbiologie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/427451793?language=en
• 关键词: Deciphering; mRNP; Code; Successful; Glia

The generation of new neurons and their functional integration into damaged neuronal circuits are the major challenges in regenerative medicine upon brain injury and neurodegeneration. A recent, revolutionary approach to convert local, reactive glial cells with the help of neurogenic factors into functionally integrated neurons represented a milestone in restoring neuronal circuitry. As conversion works at surprisingly high rates, this approach is most promising for future regenerative therapies. However, a number of obstacles, including the synaptic integration of new neurons into the pre-existing circuitry, have to be resolved in order to translate these revolutionary discoveries into the clinic.We have recently discovered that the direct conversion of glial cells to neurons requires the RNA-binding proteins (RBPs) Staufen2 (Stau2) and Pumilio2 (Pum2). Moreover, we showed that Stau2 binds two key RNAs coding for Hes1 and Sox11, both representing key neuronal transcription? factors essential for direct glia to neuron conversion. Therefore, we will investigate Stau2 and Pum2 function in implementing neuronal fate by identifying the essential set of RNA targets necessary for direct astrocyte to neuron conversion. Next, we will dissect the role of these RBPs in controlling neurogenic target RNA stability, localization and local translation during the conversion process. Moreover, we will address the specificity (and redundancy) in Stau2 and Pum2 function(s) in fate decision. Finally, we will identify additional key RBPs involved in the functional regulation of Hes1 and Sox11 mRNAs in order to understand the dynamics of mRNP assembly and their functional contribution to direct glia to neuron conversion in detail.We envision that the experiments outlined in this proposal will enable us to initiate novel strategies to improve functional integration of new neurons into damaged circuits and hence explore their potential for regenerative therapies.

新神经元的生成及其与受损神经元回路的功能整合是脑损伤和神经退行性疾病的再生医学面临的主要挑战。最近，一种革命性的方法将局部反应性胶质细胞在神经源性因子的帮助下转化为功能完整的神经元，这是恢复神经回路的一个里程碑。由于转化率高得惊人，这种方法在未来的再生治疗中最有希望。然而，为了将这些革命性的发现转化为临床应用，必须解决许多障碍，包括新神经元与原有电路的突触整合。我们最近发现，神经胶质细胞直接转化为神经元需要rna结合蛋白（rbp） Staufen2 （Stau2）和Pumilio2 （Pum2）。此外，我们发现Stau2结合了两个编码Hes1和Sox11的关键rna，这两个rna都代表了关键的神经元转录。神经胶质直接转化为神经元的关键因素。因此，我们将通过确定星形胶质细胞直接转化为神经元所需的一组基本RNA靶点来研究Stau2和Pum2在实现神经元命运中的功能。接下来，我们将剖析这些rbp在转化过程中控制神经源性靶RNA稳定性、定位和局部翻译中的作用。此外，我们将讨论在命运决定中Stau2和Pum2函数的特异性（和冗余）。最后，我们将确定参与Hes1和Sox11 mrna功能调控的其他关键rbp，以了解mRNP组装的动力学及其对指导胶质细胞向神经元转化的功能贡献。我们设想，本提案中概述的实验将使我们能够启动新的策略，以改善新神经元与受损电路的功能整合，从而探索其再生治疗的潜力。