The role of the transcription factor AKNA in neurogenesis: from development to reprogramming.

转录因子 AKNA 在神经发生中的作用：从发育到重编程。

• 批准号: 244098409
• 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: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/244098409?language=en
• 关键词: role; transcription; factor; AKNA; neurogenesis

The mechanisms of neurogenesis are crucial not only for ontogenetic and phylogenetic brain development, but also for any attempts to replace degenerated neurons. Towards identifying novel molecular mechanisms of neurogenesis we performed genome-wide expression analysis of neurogenic versus non-neurogenic progenitors both in the developing and adult forebrain. This revealed the transcription factor Akna as a proneurogenic candidate factor given its higher expression levels in neurogenesis. Indeed, first gain- and loss-of-function experiments in the developing mouse forebrain reveal a potent neurogenic role, enhancing neurogenesis upon overexpression and retaining cells in an undifferentiated state upon knock-down. Therefore we now aim in this proposal to examine the molecular and cellular basis of these phenotypes upon Akna manipulation and determine its direct down-stream targets by genome-wide expression analysis and ChIP. In addition, we shall examine its potential role in adult neurogenesis and determine its potency in direct reprogramming by introducing it into non-neuronal cells and assaying to which extent it may be sufficient to elicit neurogenesis on its own or in combination with other factors. This will allow important insights into the molecular mechanisms of neurogenesis by unraveling novel down-stream effectors of a novel neurogenic factor.

神经发生的机制不仅对个体发育和系统发育的脑发育至关重要，而且对任何试图取代退化神经元的尝试都至关重要。为了确定神经发生的新分子机制，我们对发育中和成年前脑中的神经源性与非神经源性祖细胞进行了全基因组表达分析。这揭示了转录因子Akna作为前神经发生的候选因子，因为其在神经发生中的较高表达水平。事实上，在发育中的小鼠前脑中的第一个功能获得和丧失实验揭示了一种有效的神经原性作用，在过表达时增强神经发生，并在敲低时保持细胞处于未分化状态。因此，我们现在的目标是在这个建议，以检查Akna操纵后，这些表型的分子和细胞基础，并确定其直接下游目标的全基因组表达分析和ChIP。此外，我们将研究其在成人神经发生中的潜在作用，并通过将其引入非神经元细胞并测定其自身或与其他因素结合足以引起神经发生的程度来确定其在直接重编程中的效力。这将允许重要的洞察神经发生的分子机制，通过解开新的下游效应的一种新的神经原性因子。