Glial cells make neurons: molecular mechanisms of neurogenesis

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周围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，是胶质细胞的两种主要类型之一。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识别对干细胞特征和分化为神经元至关重要的因素。决定非神经源性区域星形胶质细胞走向神经元命运的一个重要因素是转录因子Pax6。我们(Goetz)体外实验的功能分析表明，Pax6对放射状神经胶质细胞的神经生成潜力至关重要，并能够刺激星形胶质细胞分化为神经元。我们现在希望将这些发现转移到体内情况，并在不同的中枢神经系统损害范例中检测Pax6。此外，我们的目标是确定细胞表面分子介导的神经胶质细胞由Pax6启动的命运。有趣的是，细胞黏附分子L1和F3(Schachner)被确定为Pax6的靶标。它们在星形胶质细胞中的作用(包括在干细胞和成人中枢神经系统非神经源性区域的星形胶质细胞中)将在功能丧失/功能增加分析中进行研究。一方面，我们将研究成年SVZ的星形细胞干细胞在F3-/-和L1-/-小鼠海马区的神经分化潜能；另一方面，我们希望在非神经源性区域的星形胶质细胞中错误表达L1和F3，以观察它们的增殖或神经发生能力是否发生变化。其目的是识别潜在的外部刺激，使成人大脑中无处不在的星形胶质细胞在体内朝着神经元替代方向发展。为了确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神经胶质细胞的RNA图谱来确定可能的靶点，以调节治疗方面的神经生成潜力。

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.