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PreprintCited by 67RNA and protein synthesis mechanismsNeurogenesis and neuroplasticity mechanismsGenetics and Neurodevelopmental Disorders

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

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Harnett, Dermot, Ambrozkiewicz, Mateusz C., Zinnall, Ulrike, Rusanova, Alexandra, Borisova, Ekaterina, Dannenberg, Rike, Imami, Koshi, Münster-Wandowski, Agnieszka, Fauler, Beatrix, Mielke, Thorsten, Selbach, Matthias, Landthaler, Markus, Spahn, Christian M.T., Tarabykin, Victor, Ohler, Uwe, Kraushar, Matthew L.·2021·Nature Structural & Molecular Biology
DOI 10.1101/2021.06.23.449626PMC PMC9758057

Preprint — published as 10.1038/s41594-022-00882-9 · Paper page

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Abstract

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 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 number, coinciding with a major shift in protein synthesis dynamics at mid-gestation. Changing levels of eIF4EBP1, a direct inhibitor of ribosomal protein translation, are concurrent with ribosome downregulation and controls Satb2 fate acquisition during neuronal differentiation. Thus, the refinement of transcriptional programs by translation is central to the molecular logic of brain development. Modeling of the developmental neocortex translatome is provided as an open-source searchable resource: https://shiny.mdc-berlin.de/cortexomics/ .

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Metadata

Authors
Harnett, D., Ambrozkiewicz, M. C., Zinnall, U., Rusanova, A., Borisova, E., Dannenberg, R., Imami, K., Münster-Wandowski, A., Fauler, B., Mielke, T., Selbach, M., Landthaler, M., Spahn, C. M. T., Tarabykin, V., Ohler, U., & Kraushar, M. L.
Affiliations
  • Max Delbrück Center (DE)
  • Humboldt-Universität zu Berlin (DE)
  • N. I. Lobachevsky State University of Nizhny Novgorod (RU)
  • Max Planck Institute for Molecular Genetics (DE)
  • Charité – Universitätsmedizin Berlin (DE)
Corresponding author
  • Harnett, Dermot
  • Ambrozkiewicz, Mateusz C.
  • Kraushar, Matthew L.
ORCID
Venue
Nature Structural & Molecular Biology
Publisher
openRxiv
Published
2021-06-24
Volume
29
Issue
12
Pages
1277-1290
ISSN
1545-9985 (ISSN-L)
DOI
10.1101/2021.06.23.449626
PMC
PMC9758057
OpenAlex
W3209377899
Cited by
67
References
3
Citations by year
2026: 13 · 2025: 24 · 2024: 14 · 2023: 13 · 2022: 2 · 2021: 1
FWCI
4.33
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Nature Structural & Molecular Biology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (acceptedVersion)
Funders
  • Alexander von Humboldt-Stiftung
  • Deutsche Forschungsgemeinschaft
  • Max-Planck-Gesellschaft
  • Russian Science Foundation
  • Japan Society for the Promotion of Science (20H04844, 20H03241, 21H05720)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
translational regulation, brain development, ribosome biogenesis, ribosomal proteins, 4E-BP1, SATB2, neuronal lineage specification, translatome, mouse embryo, cortical development
MeSH terms
Animals, Brain, Codon, Ribosomal Proteins, Ribosomes, Protein Biosynthesis, Mice

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