Stewart Rebeccah K, Nguyen Patrick, Laederach Alain, Volkan Pelin C, Sawyer Jessica K, Fox Donald T
bioRxiv. 2023 Jul 27:2023.07.26.550700. doi: 10.1101/2023.07.26.550700.
Regulation of codon optimality is an increasingly appreciated layer of cell- and tissue-specific protein expression control. Here, we use codon-modified reporters to show that differentiation of neural stem cells into neurons enables protein expression from rare-codon-enriched genes. From a candidate screen, we identify the cytoplasmic polyadenylation element binding (CPEB) protein Orb2 as a positive regulator of rare-codon-dependent expression in neurons. Using RNA sequencing, we reveal that Orb2-upregulated mRNAs in the brain with abundant Orb2 binding sites have a rare-codon bias. From these Orb2-regulated mRNAs, we demonstrate that rare-codon enrichment is important for expression control and social behavior function of the metabotropic glutamate receptor (mGluR). Our findings reveal a molecular mechanism by which neural stem cell differentiation shifts genetic code regulation to enable critical mRNA and protein expression.
密码子最优性的调控是细胞和组织特异性蛋白质表达控制中一个日益受到重视的层面。在这里，我们使用密码子修饰的报告基因来表明神经干细胞向神经元的分化能够使富含稀有密码子的基因进行蛋白质表达。通过候选筛选，我们确定细胞质聚腺苷酸化元件结合（CPEB）蛋白Orb2是神经元中稀有密码子依赖性表达的正调控因子。使用RNA测序，我们发现大脑中具有丰富Orb2结合位点的Orb2上调的mRNA具有稀有密码子偏好性。从这些受Orb2调控的mRNA中，我们证明稀有密码子富集对于代谢型谷氨酸受体（mGluR）的表达控制和社会行为功能很重要。我们的研究结果揭示了一种分子机制，通过该机制神经干细胞分化改变遗传密码调控，以实现关键的mRNA和蛋白质表达。
