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

神经发生的机制不仅对个体发育和系统发育大脑发育至关重要，而且对任何试图取代退化神经元的尝试也是至关重要的。为了确定神经发生的新的分子机制，我们在发育中的和成人的前脑中进行了神经源性和非神经源性前体细胞的全基因组表达分析。这表明转录因子Akna在神经发生中有较高的表达水平，是一种神经发生的候选因子。事实上，在发育中的小鼠前脑中的第一个获得和功能丧失的实验揭示了一个强大的神经起源作用，在过度表达时促进神经发生，并在击倒时保留未分化的细胞状态。因此，我们现在的目标是研究这些表型在Akna操作中的分子和细胞基础，并通过全基因组表达分析和芯片来确定其直接的下游靶点。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细胞并分析其在多大程度上可能足以单独或与其他因素联合诱导神经发生来确定其在直接重编程中的效力。这将通过解开一种新的神经源性因子的新的下游效应器，从而对神经发生的分子机制有重要的见解。

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.