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.

神经发生机制不仅对于个体发育和系统发育的大脑发育至关重要，而且对于任何替代退化神经元的尝试也至关重要。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和非神经源性祖细胞进行了全基因组表达分析。这表明转录因子 Akna 在神经发生中表达水平较高，因此是一种原神经发生候选因子。事实上，在发育中的小鼠前脑中进行的首次功能获得和功能丧失实验揭示了其强大的神经发生作用，在过度表达时增强神经发生，并在敲除时将细胞保持在未分化状态。因此，我们现在的目标是在 Akna 操作下检查这些表型的分子和细胞基础，并通过全基因组表达分析和 ChIP 确定其直接下游靶点。此外，我们将检查其在成体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足以单独或与其他因素结合来引发神经发生的程度来确定其在直接重编程中的效力。通过揭示新型神经发生因子的新型下游效应器，这将有助于深入了解神经发生的分子机制。