Temporally defined neocortical translation and polysome assembly are determined by the RNA-binding protein Hu antigen R
Temporally defined neocortical translation and polysome assembly are determined by the RNA-binding protein Hu antigen R
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DOI：
10.1073/pnas.1408305111
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发表时间：
2014-09-09
影响因子：
11.1
通讯作者：
Rasin, Mladen-Roko
中科院分区：
文献类型：
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作者：
Kraushar, Matthew L.;Thompson, Kevin;Rasin, Mladen-Roko
mRNA翻译机制的精确时空控制对于新皮层等高度复杂系统的发展至关重要。然而，在发育中的新皮层中，翻译机制的时空调控仍然知之甚少。在这里，我们发现一种rna结合蛋白，Hu抗原R (HuR)，在小鼠中以发育阶段依赖的方式调节新皮质发生和新皮质翻译机制的特异性。新皮质缺乏HuR会改变核心翻译机制中起始因子和延伸因子的磷酸化状态。此外，HuR调节与功能相关的mrna在时间上特异性定位到活性翻译位点，即多聚体。HuR还通过定义核糖体蛋白和起始和延伸因子的组合组成来确定新皮质多体的特异性。对于一些依赖于HuR的蛋白，与多体的关联同样依赖于真核起始因子2 α激酶4，其在产前发育的新皮质中与HuR相关。最后，我们发现在胚胎第10天之前缺失HuR会破坏新皮质层压和主要新皮质连接体（胼胝体）的形成。我们的研究确定了HuR在新皮质发育中的关键作用，作为功能相关mRNA亚群和多体蛋白特异性的翻译守门人。
Precise spatiotemporal control of mRNA translation machinery is essential to the development of highly complex systems like the neocortex. However, spatiotemporal regulation of translation machinery in the developing neocortex remains poorly understood. Here, we show that an RNA-binding protein, Hu antigen R (HuR), regulates both neocorticogenesis and specificity of neocortical translation machinery in a developmental stage-dependent manner in mice. Neocortical absence of HuR alters the phosphorylation states of initiation and elongation factors in the core translation machinery. In addition, HuR regulates the temporally specific positioning of functionally related mRNAs into the active translation sites, the polysomes. HuR also determines the specificity of neocortical polysomes by defining their combinatorial composition of ribosomal proteins and initiation and elongation factors. For some HuR-dependent proteins, the association with polysomes likewise depends on the eukaryotic initiation factor 2 alpha kinase 4, which associates with HuR in prenatal developing neocortices. Finally, we found that deletion of HuR before embryonic day 10 disrupts both neocortical lamination and formation of the main neocortical commissure, the corpus callosum. Our study identifies a crucial role for HuR in neocortical development as a translational gatekeeper for functionally related mRNA subgroups and polysomal protein specificity.