The Rb/E2F Pathway Modulates Neurogenesis through Direct Regulation of the Dlx1/Dlx2 Bigene Cluster
The Rb/E2F Pathway Modulates Neurogenesis through Direct Regulation of the Dlx1/Dlx2 Bigene Cluster
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DOI：
10.1523/jneurosci.1344-12.2012
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发表时间：
2012-06-13
影响因子：
5.3
通讯作者：
Slack, Ruth S.
中科院分区：
文献类型：
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作者：
Ghanem, Noel;Andrusiak, Matthew G.;Slack, Ruth S.
在脑形态发生过程中，细胞周期机制与分化信号整合的机制仍然难以捉摸。在这里，我们表明，Rb/E2 F途径调节分化和迁移的关键方面，通过直接控制的Dlx 1和Dlx 2同源结构域蛋白，需要interneuron规范。Rb缺乏导致Dlx 1和Dlx 2基因表达显著减少，表现为小鼠脑中中间神经元亚型的丢失和严重的迁移缺陷。Rb/E2 F途径通过体外和体内阻遏物E2 F位点与Dlx前脑特异性增强子I12 b和Dlx 1/Dlx 2近端启动子区直接相互作用来调节Dlx 1/Dlx 2调节。在不存在Rb的情况下，我们证明阻遏物E2 Fs抑制Dlx在Dlx 1/Dlx 2启动子和Dlx 12-I12 b增强子处的转录以抑制分化。我们的研究结果支持一种模型，即细胞周期机制不仅控制细胞分裂，而且还通过直接调节Dlx 1/Dlx 2双基因簇在胚胎发育过程中调节神经元的分化和迁移。
During brain morphogenesis, the mechanisms through which the cell cycle machinery integrates with differentiation signals remain elusive. Here we show that the Rb/E2F pathway regulates key aspects of differentiation and migration through direct control of the Dlx1 and Dlx2 homeodomain proteins, required for interneuron specification. Rb deficiency results in a dramatic reduction of Dlx1 and Dlx2 gene expression manifested by loss of interneuron subtypes and severe migration defects in the mouse brain. The Rb/E2F pathway modulates Dlx1/Dlx2 regulation through direct interaction with a Dlx forebrain-specific enhancer, I12b, and the Dlx1/Dlx2 proximal promoter regions, through repressor E2F sites both in vitro and in vivo. In the absence of Rb, we demonstrate that repressor E2Fs inhibit Dlx transcription at the Dlx1/Dlx2 promoters and Dlx1/2-I12b enhancer to suppress differentiation. Our findings support a model whereby the cell cycle machinery not only controls cell division but also modulates neuronal differentiation and migration through direct regulation of the Dlx1/Dlx2 bigene cluster during embryonic development.