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: 5378307
• 负责人: Professorin Dr. Magdalena Götz
• 金额: --
• 依托单位: Institut für Physiologische Genomik
• 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 2008-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/5378307?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.

最近将成年哺乳动物中枢神经系统的神经干细胞分化为中央和周围神经系统的神经或神经胶质细胞，以及人体其他器官的细胞，是星形胶质细胞，这是两种主要类型的神经胶质细胞之一。与神经细胞相比，中枢神经系统中星形胶质细胞的频率要高得多，但是它们的干细胞特性仅限于大脑的两个小区域。这项工作的目的是鉴定因其干细胞特征和分化为神经元的因素。直接非神经发生区域星形胶质细胞到神经元命运的重要因素是转录因子PAX6。我们（Goetz）体外实验中功能的分析表明，PAX6对于径向神经胶质细胞的神经源性潜力至关重要，并且能够刺激星形胶质细胞分化为神经元。现在，我们想将这些发现转移到体内情况，并检查不同CNS病变范式中的PAX6。此外，我们的目标是介导PAX6引发的神经胶质细胞的神经源性命运的识别细胞表面分子。有趣的是，细胞粘附分子L1和F3（Schachner）被确定为PAX6的靶标。它们在星形胶质细胞（在干细胞和成年中枢神经系统的非神经生成区域的星形细胞中）中的作用都将在功能丧失/功能分析的增加时进行研究。一方面，我们将研究成年SVZ的星形细胞和F3 - / - 和L1 - / - 小鼠中海马的星形细胞的神经源性潜力。另一方面，我们希望在非神经发生区域的星形胶质细胞中Misexpress L1和F3，以查看它们的增殖或神经源能力是否发生变化。目的是识别潜在的外部刺激，以使成年大脑无处不在的星形胶质细胞在体内替代神经元替代。为了鉴定与神经发生有关的其他细胞表面分子，我们将使用神经发生和非神经胶质神经胶质细胞的RNA分析来鉴定可能针对治疗治疗的神经源性潜力的可能靶标。