4.5 Article

A critical period of translational control during brain development at codon resolution

Journal

NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 29, Issue 12, Pages 1277-+

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s41594-022-00882-9

Keywords

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Funding

  1. EMBO Long-Term Postdoctoral Fellowship [190-2016]
  2. Alexander von Humboldt Foundation Postdoctoral Fellowship
  3. International Guest Fellowship from the Max Planck Institute for Molecular Genetics
  4. Klaus Tschira Boost Fund
  5. Russian Science Foundation Basic Research grant [19-34-51009]
  6. Deutsche Forschungsgemeinschaft [DFG TA303/13-1]

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Translation plays a crucial role in modulating the timing and amplification of gene expression during brain development. This study reveals a transient window of dynamic regulation in prenatal brain, where translation upregulation of specific chromatin-binding proteins and downregulation of ribosomal proteins contribute to neuronal subtype differentiation and changes in protein synthesis dynamics. This research highlights the importance of translation in refining transcriptional programs during brain development.
Translation modulates the timing and amplification of gene expression after transcription. Brain development requires uniquely complex gene expression patterns, but large-scale measurements of translation directly in the prenatal brain are lacking. We measure the reactants, synthesis and products of mRNA translation spanning mouse neocortex neurogenesis, and discover a transient window of dynamic regulation at mid-gestation. Timed translation upregulation of chromatin-binding proteins like Satb2, which is essential for neuronal subtype differentiation, restricts protein expression in neuronal lineages despite broad transcriptional priming in progenitors. In contrast, translation downregulation of ribosomal proteins sharply decreases ribosome biogenesis, coinciding with a major shift in protein synthesis dynamics at mid-gestation. Changing activity of eIF4EBP1, a direct inhibitor of ribosome biogenesis, is concurrent with ribosome downregulation and affects neurogenesis of the Satb2 lineage. Thus, the molecular logic of brain development includes the refinement of transcriptional programs by translation. Modeling of the developmental neocortex translatome is provided as an open-source searchable resource at https://shiny.mdc-berlin.de/cortexomics.

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