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- Title
Protein translation rate determines neocortical neuron fate.
- Authors
Borisova, Ekaterina; Newman, Andrew G.; Couce Iglesias, Marta; Dannenberg, Rike; Schaub, Theres; Qin, Bo; Rusanova, Alexandra; Brockmann, Marisa; Koch, Janina; Daniels, Marieatou; Turko, Paul; Jahn, Olaf; Kaplan, David R.; Rosário, Marta; Iwawaki, Takao; Spahn, Christian M. T.; Rosenmund, Christian; Meierhofer, David; Kraushar, Matthew L.; Tarabykin, Victor
- 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. Here the authors demonstrate how protein translation, controlled by Ire1α, regulates neuronal diversification in the developing neocortex.
- Subjects
GENETIC regulation; GENETIC translation; SMALL molecules; GENETIC transcription; NEURONS; PROTEINS; INTERNEURONS
- Publication
Nature Communications, 2024, Vol 15, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-024-49198-w