Protein translation rate determines neocortical neuron fate

Ekaterina Borisova, Andrew G. Newman, Marta Couce Iglesias, Rike Dannenberg, Theres Schaub, Bo Qin, Alexandra Rusanova, Marisa Brockmann, Janina Koch, Marieatou Daniels, Paul Turko, Olaf Jahn, David R. Kaplan, Marta Rosário, Takao Iwawaki, Christian M. T. Spahn, Christian Rosenmund, David Meierhofer, Matthew L. Kraushar, Victor Tarabykin () and Mateusz C. Ambrozkiewicz ()
Additional contact information
Ekaterina Borisova: Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Andrew G. Newman: Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Marta Couce Iglesias: Max Planck Institute for Molecular Genetics
Rike Dannenberg: Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Theres Schaub: Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Bo Qin: Max Planck Institute for Molecular Genetics
Alexandra Rusanova: Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Marisa Brockmann: Charité-Universitätsmedizin Berlin
Janina Koch: Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Marieatou Daniels: Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Paul Turko: Charité-Universitätsmedizin Berlin
Olaf Jahn: Max Planck Institute for Multidisciplinary Sciences
David R. Kaplan: University of Toronto
Marta Rosário: Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Takao Iwawaki: Kanazawa Medical University
Christian M. T. Spahn: Charité-Universitätsmedizin Berlin
Christian Rosenmund: Charité-Universitätsmedizin Berlin
David Meierhofer: Max Planck Institute for Molecular Genetics
Matthew L. Kraushar: Max Planck Institute for Molecular Genetics
Victor Tarabykin: Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Mateusz C. Ambrozkiewicz: Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin

Nature Communications, 2024, vol. 15, issue 1, 1-25

Abstract: Abstract The mammalian neocortex comprises an enormous diversity regarding cell types, morphology, and connectivity. In this work, we discover a post-transcriptional mechanism of gene expression regulation, protein translation, as a determinant of cortical neuron identity. We find specific upregulation of protein synthesis in the progenitors of later-born neurons and show that translation rates and concomitantly protein half-lives are inherent features of cortical neuron subtypes. In a small molecule screening, we identify Ire1α as a regulator of Satb2 expression and neuronal polarity. In the developing brain, Ire1α regulates global translation rates, coordinates ribosome traffic, and the expression of eIF4A1. Furthermore, we demonstrate that the Satb2 mRNA translation requires eIF4A1 helicase activity towards its 5’-untranslated region. Altogether, we show that cortical neuron diversity is generated by mechanisms operating beyond gene transcription, with Ire1α-safeguarded proteostasis serving as an essential regulator of brain development.

Date: 2024
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DOI: 10.1038/s41467-024-49198-w

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