Glial cells make neurons: molecular mechanisms of neurogenesis

胶质细胞产生神经元：神经发生的分子机制

• 批准号: 5378312
• 负责人: Professorin Dr. Melitta Schachner
• 金额: --
• 依托单位: Seniorgruppe Biosynthese Neuraler Strukturen
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2002
• 资助国家: 德国
• 起止时间: 2001-12-31 至 2005-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/5378312?language=en
• 关键词: Glial; cells; make; neurons; molecular

Neural stem cells of the adult mammalian CNS which can differentiate both into nerve or glial cells of the central and peripheral nervous system and into cells of other organs of the body, were recently identified as astrocytes, one of the two main types of glial cells. The frequency of astrocytes in the CNS is much higher when compared to nerve cells, but their stem cell characteristics are restricted to two small regions of the brain. The aim of this work will be the identification of factors which are crucial for their stem cell characteristics and differentiation into neurons. An important factor to direct astrocytes of non-neurogenic regions to a neuronal fate is the transcription factor Pax6. Analysis of function in our (Goetz) in vitro experiments showed that Pax6 is crucial for the neurogenic potential of radial glial cells and is able to stimulate astrocytes to differentiate into neurons. We now want to transfer these findings to the in vivo situation and examine Pax6 in different CNS lesion paradigms. Moreover, we aim to identity cell surface molecules mediating the neurogenic fate of glial cells initiated by Pax6. Interestingly, the cell adhesion molecules L1 and F3 (Schachner) were identified as targets of Pax6. Their role in astrocytes (both in stem cells and in astrocytes of non-neurogenic regions of the adult CNS) will be investigated in loss of function/increase of function analyses. On the one hand, we will investigate the neurogenic potential of the astrocytic stem cells of the adult SVZ and the hippocampus in F3 -/- and L1 -/- mice; on the other hand we want to misexpress L1 and F3 in astrocytes of non-neurogenic regions to see if there is a change in their proliferative or neurogenic capacity. The aim is to identify potential extrinsic stimuli that allow directing the ubiquitous astrocytes of the adult brain towards neuronal replacement in vivo. To identify additional cell surface molecules implicated in neurogenesis, we will use RNA profiling of neurogenic and non-neurogenic glial cells to identify possible targets for the regulation of the neurogenic potential with regard to therapeutic treatments.

成年哺乳动物中枢神经系统的神经干细胞可以分化为中枢和外周神经系统的神经或神经胶质细胞，也可以分化为身体其他器官的细胞，最近被鉴定为星形胶质细胞，是两种主要类型的神经胶质细胞之一。与神经细胞相比，星形胶质细胞在CNS中的频率要高得多，但它们的干细胞特征仅限于大脑的两个小区域。这项工作的目的将是确定的因素是至关重要的干细胞的特性和分化成神经元。将非神经源性区域的星形胶质细胞导向神经元命运的重要因子是转录因子Pax 6。我们（Goetz）体外实验中的功能分析表明，Pax 6对放射状胶质细胞的神经发生潜力至关重要，并且能够刺激星形胶质细胞分化为神经元。我们现在想将这些发现转移到体内情况，并在不同的CNS病变范例中检查Pax 6。此外，我们的目标是识别介导由Pax 6启动的神经胶质细胞的神经发生命运的细胞表面分子。有趣的是，细胞粘附分子L1和F3（Schachner）被鉴定为Pax 6的靶点。将在功能丧失/功能增加分析中研究其在星形胶质细胞（干细胞和成人CNS非神经源性区域的星形胶质细胞）中的作用。一方面，我们将研究F3 -/-和L1 -/-小鼠中成年SVZ和海马的星形胶质细胞干细胞的神经原性潜力;另一方面，我们想在非神经原性区域的星形胶质细胞中错误表达L1和F3，以观察其增殖或神经原性能力是否发生变化。其目的是确定潜在的外源性刺激，使无处不在的星形胶质细胞的成人大脑神经元替代体内。为了鉴定与神经发生有关的其他细胞表面分子，我们将使用神经源性和非神经源性胶质细胞的RNA分析来鉴定调节神经源性潜能的可能靶点。