A critical period of translational control during brain development at codon resolution
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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 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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- Authors
- Harnett, D., Ambrozkiewicz, M. C., Zinnall, U., Rusanova, A., Borisova, E., Drescher, A. N., Couce-Iglesias, M., Villamil, G., 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
- Published
- 2022-12
- Volume
- 29
- Issue
- 12
- Pages
- 1277-1290
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- PMC
- PMC9758057
- OpenAlex
- W3209377899
- Cited by
- 68
- References
- 14
- Citations by year
- 2026: 14 · 2025: 24 · 2024: 14 · 2023: 13 · 2022: 2 · 2021: 1
- FWCI
- 4.31
- Type
- journal article
- Language
- en
- Update notices
- correction (2025-08-27)
- Open access
- hybrid
- doi.org
- 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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