Gene regulation logic in retinal ganglion cell development: Isl1 defines a critical branch distinct from but overlapping with Pou4f2
Gene regulation logic in retinal ganglion cell development: Isl1 defines a critical branch distinct from but overlapping with Pou4f2
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DOI：
10.1073/pnas.0802627105
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发表时间：
2008-05-13
影响因子：
11.1
通讯作者：
Klein, William H.
中科院分区：
文献类型：
--
作者：
Mu, Xiuqian;Fu, Xueyao;Klein, William H.
了解控制神经元分化的基因调控网络（GRNs）将为神经发生提供系统水平的视角。我们以前已经构建了一个模型，在视网膜神经节细胞（RGC）分化的四个层次的转录因子最终控制下游终端基因的表达的GRN。Math5在层次结构中占据中心节点，因为它对于RGC的形成和直接下游因子Pou4f2的表达至关重要。基于它的表达，我们还提出，Isl1，一个LIM-homeodomain因子，在RGC GRN中与Pou4f2和Math5下游平行发挥作用。为了确定是否是这种情况下，条件Isl1等位基因产生和删除，特别是在发展中的视网膜。虽然RGCs形成Isl1缺失的视网膜，大多数发生凋亡，很少留在后期阶段。通过微阵列分析，我们确定了一组独特的基因，其表达依赖于Isl1。这些基因都位于Math5的下游，其中一些（但不是全部）也依赖于Pou4f2。此外，Pou4f2的持续表达需要Isl1，这表明Isl1在Math5水平降低后正调控Pou4f2。结果表明，Isl1在RGC发展中起着重要作用，并揭示了Math5下游RGC GRN的两个不同但交叉的分支，一个由Pou4f2指导，另一个由Isl1指导。他们还揭示了相同的RGC表达模式是通过来自上游转录因子的不同输入的不同组合来实现的。
Understanding gene regulatory networks (GRNs) that control neuronal differentiation will provide systems-level perspectives on neurogenesis. We have previously constructed a model for a GRN in retinal ganglion cell (RGC) differentiation in which four hierarchical tiers of transcription factors ultimately control the expression of downstream terminal genes. Math5 occupies a central node in the hierarchy because it is essential for the formation of RGCs and the expression of the immediate downstream factor Pou4f2. Based on its expression, we also proposed that Isl1, a LIM-homeodomain factor, functions in parallel with Pou4f2 and downstream of Math5 in the RGC GRN. To determine whether this was the case, a conditional Isl1 allele was generated and deleted specifically in the developing retina. Although RGCs formed in Isl1-deleted retinas, most underwent apoptosis, and few remained at later stages. By microarray analysis, we identified a distinct set of genes whose expression depended on Isl1. These genes are all downstream of Math5, and some of them, but not all, also depend on Pou4f2. Additionally, Isl1 was required for the sustained expression of Pou4f2, suggesting that Isl1 positively regulates Pou4f2 after Math5 levels are diminished. The results demonstrate an essential role for Isl1 in RGC development and reveal two distinct but intersecting branches of the RGC GRN downstream of Math5, one directed by Pou4f2 and the other by Isl1. They also reveal that identical RGC expression patterns are achieved by different combinations of divergent inputs from upstream transcription factors.