Stemness factor Mex3a times translation and protein trafficking to ensure robust differentiation of olfactory sensory neurons [HyperTRIBE]

During the switch from progenitor to terminally differentiated cell, cellular physiology must change to accommodate increased translation and trafficking of membrane-bound proteins. We identify stemness factor Mex3a, expressed in immature olfactory sensory neurons (OSNs), as a key factor in ensuring proper neuronal differentiation by regulating translation and trafficking of cell surface proteins in the context of Unfolded Protein Response (UPR) signaling. Loss of Mex3a in immature OSNs leads to defects in cilia structure, cell surface protein expression, and planar cell polarity in mature OSNs. Proteomics reveal a decrease in proteins related to vesicle organization. We identify putative RNA and ubiquitin targets of Mex3a and provide evidence that Mex3a can confer K27 ubiquitin linkage on targets. Finally, modulating cellular levels of Mex3a changes the recruitment of translational elongation factors to ribosomes with effects on translation. Our data reveal how a stemness factor regulates development post-transcriptionally and post-translationally to ensure robust differentiation.