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Mapping gene regulatory circuitry of Pax6 during neurogenesis

机译：在神经发生过程中定位Pax6的基因调控电路

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Pax6 is a highly conserved transcription factor among vertebrates and is important in various aspects of the central nervous system development. However, the gene regulatory circuitry of Pax6 underlying these functions remains elusive. We find that Pax6 targets a large number of promoters in neural progenitors cells. Intriguingly, many of these sites are also bound by another progenitor factor, Sox2, which cooperates with Pax6 in gene regulation. A combinatorial analysis of Pax6-binding data set with transcriptome changes in Pax6-deficient neural progenitors reveals a dual role for Pax6, in which it activates the neuronal (ectodermal) genes while concurrently represses the mesodermal and endodermal genes, thereby ensuring the unidirectionality of lineage commitment towards neuronal differentiation. Furthermore, Pax6 is critical for inducing activity of transcription factors that elicit neurogenesis and repress others that promote non-neuronal lineages. In addition to many established downstream effectors, Pax6 directly binds and activates a number of genes that are specifically expressed in neural progenitors but have not been previously implicated in neurogenesis. The in utero knockdown of one such gene, Ift74 , during brain development impairs polarity and migration of newborn neurons. These findings demonstrate new aspects of the gene regulatory circuitry of Pax6, revealing how it functions to control neuronal development at multiple levels to ensure unidirectionality and proper execution of the neurogenic program.
机译：Pax6是脊椎动物中高度保守的转录因子，在中枢神经系统发育的各个方面都非常重要。但是，这些功能背后的Pax6的基因调控电路仍然难以捉摸。我们发现Pax6靶向神经祖细胞中的大量启动子。有趣的是，这些位点中的许多位点还受到另一个祖细胞因子Sox2的约束，该因子与Pax6在基因调控中协同作用。 Pax6结合数据集与Pax6缺陷型神经祖细胞转录组变化的组合分析揭示了Pax6的双重作用，即它激活神经元（外胚层）基因，同时抑制中胚层和内胚层基因，从而确保谱系的单向性对神经元分化的承诺。此外，Pax6对于诱导引起神经发生并抑制其他促进非神经元谱系的转录因子的活性至关重要。除了许多已建立的下游效应子外，Pax6还直接结合并激活了许多基因，这些基因在神经祖细胞中特异性表达，但以前并未参与神经发生。大脑发育过程中一种这样的基因Ift74在子宫内的敲低会损害新生儿神经元的极性和迁移。这些发现证明了Pax6基因调控电路的新方面，揭示了它如何在多个水平上控制神经元发育，以确保神经元程序的单向性和正确执行。

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