Regulation of translation during human development is poorly understood, and its dysregulation is associated with Rett syndrome (RTT). To discover shifts in mRNA ribosomal engagement (RE) during human neurodevelopment, we use parallel translating ribosome affinity purification sequencing (TRAP-seq) and RNA sequencing (RNA-seq) on control and RTT human induced pluripotent stem cells, neural progenitor cells, and cortical neurons. We find that 30% of transcribed genes are translationally regulated, including key gene sets (neurodevelopment, transcription and translation factors, and glycolysis). Approximately 35% of abundant intergenic long noncoding RNAs (lncRNAs) are ribosome engaged. Neurons translate mRNAs more efficiently and have longer 3ʹ UTRs, and RE correlates with elements for RNA-binding proteins. RTT neurons have reduced global translation and compromised mTOR signaling, and >2,100 genes are translationally dysregulated. NEDD4L E3-ubiquitin ligase is translationally impaired, ubiquitinated protein levels are reduced, and protein targets accumulate in RTT neurons. Overall, the dynamic translatome in neurodevelopment is disturbed in RTT and provides insight into altered ubiquitination that may have therapeutic implications.

人们对人类发育过程中的翻译调节知之甚少，其失调与雷特综合征 (RTT) 相关。为了发现人类神经发育过程中 mRNA 核糖体参与 (RE) 的变化，我们在对照和 RTT 人类诱导多能干细胞、神经祖细胞和皮质神经元。我们发现 30% 的转录基因受到翻译调控，包括关键基因集（神经发育、转录和翻译因子以及糖酵解）。大约 35% 的丰富的基因间长非编码 RNA (lncRNA) 参与了核糖体。神经元更有效地翻译 mRNA，并具有更长的 3ʹ UTR，并且 RE 与 RNA 结合蛋白的元件相关。RTT 神经元减少了全局翻译并破坏了 mTOR 信号，并且超过 2,100 个基因在翻译上失调。NEDD4L E3-泛素连接酶翻译受损，泛素化蛋白质水平降低，蛋白质靶点在 RTT 神经元中积累。总体而言，神经发育中的动态翻译组在 RTT 中受到干扰，并提供了对可能具有治疗意义的泛素化改变的洞察。