A critical period of translational control during brain development at codon resolution

Abstract

Translation modulates the timing and amplification of gene expression after transcription. Development of the brain's neocortex requires precisely timed and spatially targeted gene expression, but the relationship between mRNA vs. protein synthesis throughout the genome is unknown. We perform a comprehensive analysis of the reactants, synthesis, and products of mRNA translation spanning mouse neocortex neurogenesis. Ribosome number in the cortical plate decreases sharply at mid-neurogenesis during a transition in neuronal subtype specification, shifting the fundamental kinetics of protein synthesis, with mRNA and protein levels frequently divergent. Satb2, which drives an essential neuronal subtype-specific program, is a highly dynamically translated mRNA with surprisingly broad transcription across diverse neuronal lineages. Satb2 protein achieves its neuronal subtype expression through timed regulation by the RNA-binding protein Pumilio2. Thus, the refinement of transcriptional programs by protein synthesis is a widespread feature of neuronal specification. Developmental neocortex translatome data are provided in an open-source resource: https://shiny.mdc-berlin.de/cortexomics/.

Aberrant cortical development is driven by impaired cell cycle and translational control in a DDX3X syndrome model

“…Using Ribo-seq, we have generated a valuable new resource for understanding translation at the onset of neurogenesis. To our knowledge, this is one of the first reports to assess wildtype translation using Ribo-seq at the onset of neurogenesis, with exception of a recent pre-print which examined later stages of development ( Harnett et al, 2021 ). scRNAseq studies have revealed that transcripts important for deep and superficial layer neuronal fates are expressed in RGCs Telley et al, 2019 ; however, it’s generally thought that these are translationally repressed until neurons are born.…”

7q11.23 CNV alters protein synthesis and REST-mediated neuronal intrinsic excitability

“…The expression of ribosomal proteins decreases during neuronal differentiation (Harnett et al, 2021; Slomnicki et al, 2016). However, the molecular mechanism of how this coordinated regulation occurs remains elusive.…”

A specialized mRNA translation circuit instated in pluripotency presets the competence for cardiogenesis in humans

“…In this regard, most research efforts over the last decades have concentrated on morphogen signaling, epigenetic, and transcriptional mechanisms (Gifford et al, 2013; Loh et al, 2016; Peng et al, 2019; Rogers and Schier, 2011; Stadhouders et al, 2019). However, selective translational control is arguably the primary determinant of regulatory protein abundance in mammals and thus proposed as a central regulator of embryonic cell fate decisions (Harnett et al, 2021; Kong and Lasko, 2012; Kristensen et al, 2013; Lu et al, 2009; Schwanhausser et al, 2011; Teixeira and Lehmann, 2019). Yet, how the developmental transcriptome is selectively translated to authorize cell fate decisions is a fundamental question that remains unclear.…”