Protein translation rate determines neocortical neuron fate

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 Ire1a as a regulator of Satb2 expression and neuronal polarity. In the developing brain, Ire1a 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 Ire1a-safeguarded proteostasis serving as an essential regulator of brain development. Total RNAseq from P0 Cortices from wild-type and IRE1aEmx1Cre mutant mice as well as RNAseq from purified Polysomes from wild type and IRE1aEmx1Cre mice. 3 batches: Batch 1: Total RNAseq from cortex Batch 2: Total RNAseq from Purified Polysomes Batch 3: Total RNAseq from Purified Light and Heavy Polysomes Analysis scripts can be seen at: https://github.com/qoldt/IRE1aKO_Polysome_RNAseq