Excitatory neurons and glial cells are produced by multipotent neural progenitors as the human cerebral cortex develops. Extensive spatiotemporal gene regulatory networks that direct mammalian corticogenesis have been discovered through studies employing mouse model systems, human fetal tissues, and brain organoids. The significance of posttranscriptional gene regulatory mechanisms, such as alternative splicing and translational repression, in regulating progenitor cell fate and neuronal migration, is an emerging theme from investigations on mouse corticogenesis. It remains unclear if comparable pathways contribute to human neurodevelopment and how posttranscriptional factors affect protein abundance and gene expression during human corticogenesis.

The authors investigated this by isolating neural progenitors and neurons from human telencephalic brain organoids developed using a dual reporter cell line, performing cell class and developmental stage-specific transcriptome analysis, and proteome analysis. The two datasets were combined to show gene expression modules during human corticogenesis. Investigation of one of these modules revealed that early progenitor cells have mTOR-mediated translation regulation of the 5’TOP mRNAs encoding some of the translation machinery. They demonstrate that partial suppression of ribosomal gene translation in early progenitors avoids the premature translation of differentiation markers. In summary, the novel posttranscriptional regulatory mechanisms proposed by their multiomics approach are essential for the accuracy of cortical development.