文章基本信息

标题：Temporally defined neocortical translation and polysome assembly are determined by the RNA-binding protein Hu antigen R
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作者：Matthew L. Kraushar ; Kevin Thompson ; H. R. Sagara Wijeratne 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：36
页码：E3815-E3824
DOI：10.1073/pnas.1408305111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceThe neocortex is an intricate and diverse cellular network in the brain, generating complex thought and voluntary motor behavior. Although recent attention has focused on the genome and transcriptome, our goal is to study the role of posttranscriptional processing and mRNA translation in neocortical development. In this work, we show that the protein components of actively translating ribosomes and their mRNA cargo in the developing neocortex depend on the temporally specific action of an RNA-binding protein, Hu antigen R (HuR). We further show that HuR is required for the development of neocortical neurons and structure. This study contributes to our overall understanding of how the regulation of functional gene expression influences neocortical development. 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.
关键词：ribosome ; posttranscriptional regulation ; profiling ; GCN2 ; Elav