RNA abundance is controlled by rates of synthesis and degradation. Although mis-regulation of RNA turnover is linked to neurodevelopmental disorders how it contributes to cortical development is largely unknown. Here we discover the landscape of RNA stability regulation in the cerebral cortex and demonstrate that intact RNA decay machinery is essential for corticogenesis in vivo. We use SLAM-seq to measure RNA half-lives transcriptome-wide across multiple stages of cortical development. Leveraging these data we discover cis-acting features associated with RNA stability and probe the relationship between RNA half-life and developmental expression changes. Notably RNAs that are up-regulated across development tend to be more stable while down-regulated RNAs are less stable. Using compound mouse genetics we discover CNOT3 a core component of the CCR4-NOT deadenylase complex linked to neurodevelopmental disease is essential for cortical development. Conditional knockout of Cnot3 in neural progenitors and their progeny in the developing mouse cortex leads to severe microcephaly due to altered cell fate and p53-dependent apoptosis. Finally we define the molecular targets of CNOT3 revealing it controls expression of poorly expressed non-optimal mRNAs in the cortex including cell cycle-related transcripts. Collectively our findings demonstrate that fine-tuned control of RNA turnover is crucial for brain development.\ Please see ReadMe files for full descriptions of methodology and data generation.
