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.

新的神经元的产生及其在受损神经元电路中的功能整合是脑损伤和神经变性的再生医学中的主要挑战。一种最近的革命性方法，借助于神经源性因素将局部反应性神经胶质细胞转换为功能整合的神经元，这是恢复神经元电路的里程碑。由于转化率以惊人的速度起作用，这种方法对于将来的再生疗法是最有希望的。但是，必须解决许多障碍，包括将新神经元的突触整合到现有的电路中，以将这些革命性发现转化为诊所。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（RBPS（RBPS）Staufen2（staUioio）和Pumioio2（Pumioio）2（Pumioio）2（pumioio）此外，我们表明STAU2结合了Hes1和Sox11编码的两个密钥RNA，都代表关键的神经元转录？直接神经元转换至关重要的因素。因此，我们将通过确定直接星形胶质细胞到神经元转化所需的必需的RNA靶标，研究STAU2和PUM2在实现神经元命运方面的功能。接下来，我们将剖析这些RBP在转换过程中控制神经源靶标的RNA稳定性，定位和局部翻译中的作用。此外，我们将在命运决策中解决STAU2和PUM2功能中的特异性（和冗余）。 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.