Mutations in distinct translation-dependent quality control pathways lead to convergent molecular pathogenesis and neurodevelopmental defects.

Translation-dependent quality control pathways govern protein synthesis and proteostasis by degrading potentially toxic peptide products derived from aberrant mRNAs. However, little is known about the in vivo defects that arise in the absence of these pathways and how translation is altered in the absence of these pathways. Here, we demonstrate that the ribosome rescue factors Pelo/Hbs1l are both critical for embryonic and neuronal development but dispensable for neuronal survival in the adult brain. Loss of Pelo/Hbs1l in cerebellar progenitors impaired differentiation of these cells. Our analysis of Pelo/Hbs1l deficient fibroblasts revealed translational reprogramming of multiple pathways including mTORC1 signaling likely to restore cellular homeostasis. Interestingly, similar affects on the translatome, signaling pathways and neurogenesis were observed when we conditionally deleted Upf2 to inhibit NMD. These data reveal that translation-dependent quality control pathways, which set out to mitigate errors in translation and to clear defective peptide products and aberrant mRNAs can trigger similar cellular responses and neurodevelopmental abnormalities. Overall design: 41 samples are analyzed in this study which include RNA-seq and Ribosome footprint profiling data from mouse tissues with knockouts of different translation-dependent quality control genes. Profiling datasets include 3 replicates of Hbs1l global knockout from whole mouse embryos with paired wildtype controls. Ribosome profiling datasets also include 3 replicates of Hbs1l conditional knockout in cerebellum with matched wildtype controls. There are also RNA-seq and ribosome footprint profiling for Cre-induced knockouts from mouse embryonic fibroblasts of Pelo, Hbs1l, and Upf2, as well as Cre control samples. There are 3 replicates each with the exception of a Pelo RNA-seq sample which was excluded due to being a biological outlier. The matched Cre controls for profiling datasets are included with knockouts in each batch.