mRNA stability fine-tunes gene expression in the developing cortex to control neurogenesis

Area of Science:

• Neuroscience
• Molecular Biology
• Developmental Biology

Background:

• RNA abundance is regulated by synthesis and degradation rates.
• Dysregulation of RNA turnover is implicated in neurodevelopmental disorders.
• The role of RNA turnover in cortical development remains largely unexplored.

Purpose of the Study:

• To investigate the landscape of RNA stability regulation in the developing cerebral cortex.
• To determine the necessity of RNA decay machinery for corticogenesis.
• To identify key regulators of RNA stability in brain development.

Main Methods:

• SLAM-seq was employed for transcriptome-wide measurement of RNA half-lives across cortical development stages.
• Computational analysis identified cis-acting features governing RNA stability.
• Conditional knockout mouse models were used to assess the in vivo function of CNOT3.

Main Results:

• A correlation was found between developmental expression changes and RNA stability: upregulated RNAs were more stable, while downregulated RNAs were less stable.
• Conditional knockout of CNOT3, a component of the CCR4-NOT deadenylase complex, resulted in severe microcephaly.
• CNOT3 knockout led to altered cell fate and p53-dependent apoptosis in the developing cortex.
• CNOT3 was found to regulate poorly expressed mRNAs, including cell cycle-related transcripts.

Conclusions:

• Intact RNA decay machinery is essential for proper corticogenesis.
• CNOT3 plays a critical role in cortical development by controlling RNA stability.
• Fine-tuned regulation of RNA turnover is crucial for normal brain development.