Olfactory receptor (OR) expression requires the transcriptional activation of 1 out of 1,000s of OR alleles and a feedback signal that preserves this transcriptional choice. The mechanism by which olfactory sensory neurons (OSNs) detect ORs to signal to the nucleus remains elusive. Here, we show that OR proteins generate this feedback by activating the unfolded protein response (UPR). OR expression induces Perk-mediated phosphorylation of the translation initiation factor eif2α causing selective translation of activating transcription factor 5 (ATF5). ATF5 induces the transcription of adenylyl cyclase 3 (Adcy3), which relieves the UPR. Our data provide a role for the UPR in defining neuronal identity and cell fate commitment and support a two-step model for the feedback signal: (1) OR protein, as a stress stimulus, alters the translational landscape of the OSN and induces Adcy3 expression; (2), Adcy3 relieves that stress, restores global translation, and makes OR choice permanent.
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