GSE123753
Shifts in Ribosome Engagement Impact Key Gene Sets in Neurodevelopment and Rett Syndrome Neurons
Regulation of translationduring early human development is poorly understood anditsdysregulation is associated with disease. To discover shifts in mRNA ribosomal engagement (RE) that occur during human neurodevelopment and disease, we used parallel TRAPSeq and RNASeq on control and Rett syndrome (RTT) human induced pluripotent stem cells,neural progenitor cells and cortical neurons. We found 30% of transcribed genes were translationally regulatedincluding key gene sets (neurodevelopment, transcription and translation factors, glycolysis). Neurons more efficiently translated global mRNAs,had longer 3`UTRs and RE correlated with RNA-binding protein motif composition.In contrast, RTT neurons had reduced global translation,compromised mTOR signalingand 2100 genes were translationally dysregulated. NEDD4L E3-ubiquitin ligasewas most translationally impaired, and its protein targets accumulatedin RTT neurons. Our findings reveal a dynamic translatome in neurodevelopment, show that MECP2 regulatestranslationandubiquitin enzymes in neurons, and provide novel insight into altered proteostasis that may have therapeutic implications for RTT. Overall design: Human WT iPSCs, iPSC-derived NPCs and Neurons were subjected to TRAP-seq and RNA-seq to characterize changes in ribosome engagement during human neurodevelopment. NPCs and Neurons derived from an isogenic iPSC line containing a deletion of the MECP2 gene were also included to study changes ribosome engagement in Rett syndrome.