Mex3a-dependent post-transcriptional silencing assures olfactory receptor diversity and axon guidance specificity [Ribo-Seq]

Singular olfactory receptor (OR) expression is critical for vertebrate olfaction because the sequence of the chosen OR protein determines both the receptive field and axon guidance properties of each olfactory sensory neuron (OSN). However, numerous single cell RNA-seq studies reveal that OSN progenitors co-transcribe seemingly random combinations of OR genes before a gradual transition to transcriptional singularity. Here, we show that MEX3A, a RING and KH domain protein expressed during polygenic OR transcription, prevents efficient OR protein expression before the emergence of a prevalent, transcriptionally dominant OR allele. Consequently, MEX3A deletion enhances OR mRNA and OR protein abundance in OSN progenitors, resulting in premature induction of Perk signaling, biased OR gene choice, and OSN axon mistargeting. Our experiments uncover a novel, post-transcriptional mechanism of OR gene regulation that assures that the identity of the expressed OR can influence the identity of the OSN only at the onset of singular OR choice.单一嗅觉受体（olfactory receptor, OR）的表达对于脊椎动物嗅觉感知至关重要，因为所选OR蛋白的序列决定了每一个嗅觉感觉神经元（olfactory sensory neuron, OSN）的感受野与轴突导向特性。然而，大量单细胞RNA测序（single cell RNA-seq）研究显示，嗅觉感觉神经元祖细胞在逐步转向转录单一化进程之前，会共转录看似随机的多组OR基因组合。本研究发现，MEX3A作为一种在多基因OR转录阶段表达的RING结构域与KH结构域蛋白，可在优势转录的显性OR等位基因出现前，有效抑制OR蛋白的表达。因此，敲除MEX3A可提升嗅觉感觉神经元祖细胞中OR mRNA与OR蛋白的丰度，进而过早激活Perk信号通路、引发偏向性OR基因选择以及嗅觉感觉神经元轴突靶向错误。本研究揭示了一种全新的OR基因转录后调控机制，该机制确保仅在单一OR基因选择的起始阶段，表达的OR的分子特性才能决定嗅觉感觉神经元的细胞身份。