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首页> 外文期刊>Development >Reprogramming amacrine and photoreceptor progenitors into retinal ganglion cells by replacing Neurod1 with Atoh7
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Reprogramming amacrine and photoreceptor progenitors into retinal ganglion cells by replacing Neurod1 with Atoh7

机译：通过用Atoh7替代Neurod1将amacrine和感光受体祖细胞重编程为视网膜神经节细胞

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The specification of the seven retinal cell types from a common pool of retina progenitor cells (RPCs) involves complex interactions between the intrinsic program and the environment. The proneural basic helix-loop-helix (bHLH) transcriptional regulators are key components for the intrinsic programming of RPCs and are essential for the formation of the diverse retinal cell types. However, the extent to which an RPC can re-adjust its inherent program and the mechanisms through which the expression of a particular bHLH factor influences RPC fate is unclear. Previously, we have shown that Neurod1 inserted into the Atoh7 locus activates the retinal ganglion cell (RGC) program in Atoh7-expressing RPCs but not in Neurod1-expressing RPCs, suggesting that Atoh7-expressing RPCs are not able to adopt the cell fate determined by Neurod1, but rather are pre-programmed to produce RGCs. Here, we show that Neurod1-expressing RPCs, which are destined to produce amacrine and photoreceptor cells, can be re-programmed into RGCs when Atoh7 is inserted into the Neurod1 locus. These results suggest that Atoh7 acts dominantly to convert a RPC subpopulation not destined for an RGC fate to adopt that fate. Thus, Atoh7-expressing and Neurod1-expressing RPCs are intrinsically different in their behavior. Additionally, ChIP-Seq analysis identified an Atoh7-dependent enhancer within the intronic region of Nrxn3. The enhancer recognized and used Atoh7 in the developing retina to regulate expression of Nrxn3, but could be forced to use Neurod1 when placed in a different regulatory context. The results indicate that Atoh7 and Neurod1 activate distinct sets of genes in vivo, despite their common DNA-binding element.
机译：从共同的视网膜祖细胞（RPC）池中确定七种视网膜细胞类型涉及内在程序与环境之间的复杂相互作用。 proneural基本螺旋-环-螺旋（bHLH）转录调节因子是RPC内在编程的关键组成部分，对于形成各种视网膜细胞类型至关重要。但是，RPC可以重新调整其固有程序的程度以及特定bHLH因子的表达影响RPC命运的机制尚不清楚。以前，我们已经表明，插入Atoh7基因座的Neurod1会激活表达Atoh7的RPC中的视网膜神经节细胞（RGC）程序，但不会激活表达Neurod1的RPC中的视网膜神经节细胞，这表明表达Atoh7的RPC无法采用由Neurod1，而是预先编程以生成RGC。在这里，我们显示了将Atoh7插入Neurod1基因座时，表达Neurod1的RPC（注定会产生无长突细胞和感光细胞）可以重新编程为RGC。这些结果表明，Atoh7的主要作用是转换一个注定不是RGC命运的RPC亚群来采用该命运。因此，表达Atoh7的和表达Neurod1的RPC的行为本质上是不同的。此外，ChIP-Seq分析鉴定了Nrxn3内含子区域内依赖Atoh7的增强子。增强子识别并在发育中的视网膜中使用Atoh7来调节Nrxn3的表达，但是当置于不同的调节环境中时，可能被迫使用Neurod1。结果表明，尽管Atoh7和Neurod1具有共同的DNA结合元件，但它们在体内激活了不同的基因集。

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