Temporally defined neocortical translation and polysome assembly are determined by the RNA-binding protein Hu antigen R

Proc Natl Acad Sci U S A. 2014 Sep 9;111(36):E3815-24. doi: 10.1073/pnas.1408305111. Epub 2014 Aug 25.

Abstract

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.

Keywords: Elav; GCN2; posttranscriptional regulation; profiling; ribosome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Corpus Callosum / embryology
  • Corpus Callosum / metabolism
  • ELAV Proteins / metabolism*
  • ELAV-Like Protein 1
  • Eukaryotic Initiation Factor-2 / metabolism
  • Gene Deletion
  • Gene Knockout Techniques
  • Mice
  • Mitosis
  • Models, Biological
  • Neocortex / embryology
  • Neocortex / metabolism*
  • Neural Stem Cells / cytology
  • Neural Stem Cells / metabolism
  • Neuroepithelial Cells / metabolism
  • Neurogenesis
  • Neuroglia / metabolism
  • Neurons / metabolism
  • Phosphorylation
  • Polyribosomes / metabolism*
  • Protein Biosynthesis*
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins / metabolism*
  • Ribosomal Proteins / metabolism
  • Time Factors
  • Transcription, Genetic

Substances

  • ELAV Proteins
  • ELAV-Like Protein 1
  • ELAVL1 protein, human
  • Eukaryotic Initiation Factor-2
  • RNA, Messenger
  • RNA-Binding Proteins
  • Ribosomal Proteins
  • Eif2ak4 protein, mouse
  • Protein-Serine-Threonine Kinases

Associated data

  • GEO/GSE50809