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Protein translation rate determines neocortical neuron fate

ABSTRACT: The mammalian neocortex comprises enormous diversity regarding cell types, morphology, and connectivity. In this work, we discover a unique sensitivity in the development of neurons expressing Satb2, a determinant of upper cortical layers, to translation rates. We find specific upregulation of protein synthesis in the progenitors of later-born neurons and show that translation rates are inherent features of cortical neuron subtypes. In a small molecule screening, we reveal Ire1a as a regulator of Satb2 and global translation rates. In the developing brain, Ire1a coordinates ribosome traffic and the expression of eIF4A1. Furthermore, we demonstrate that the mRNA translation of Satb2 depends on its 5’-untranlsated region and requires eIF4A1 helicase activity. Here, we show that cortical neuron diversity is generated by mechanisms operating beyond the gene transcription, with Ire1a-safeguarded proteostasis serving as an essential regulator of brain development factors, and ribosomal proteins. Translation rates distinguish early and late neuronal progenitors and early- and late-born postmitotic neurons, indicative of developmental stage- and differentiation-specific requirements for protein synthesis rates in the formation of upper and deeper cortical layers. We demonstrate that specification and polarization of upper layer neurons is uniquely sensitive to translation rate, in contrast to deep layer neurons. Our data shed light onto the post-transcriptional source of cellular diversity in the developing cortex and unveils stress-independent homeostatic functions of Ire1a.

ORGANISM(S): Mus musculus

PROVIDER: GSE172489 | GEO | 2024/01/10

REPOSITORIES: GEO

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