TEX15 safeguards neuronal diversity in the mouse olfactory system

Animals detect diverse chemicals using hundreds of chemoreceptor proteins. In many organisms, sensory chemoreceptors obey a one-receptor-type-per-cell rule, which organizes information gathered by sensory neurons ¹ . A key question remains how receptor expression gets diversified so that hundreds of chemoreceptors get expressed across the population of sensory neurons ^2-4 . Here we show that diverse odorant receptor (OR) expression in mice depends on testis expressed gene 15 ( Tex15 ). We find that Tex15 regulates OR expression in neuronal precursor cells. In Tex15 deficient ( Tex15-/- ) mice, OR transcript levels are increased in precursors, a handful of early-transcribed OR genes get expressed at abnormally high levels, and these ORs come to dominate the olfactory sensory neuron population. This results in a profound reduction in the diversity of OR gene choice as well as disrupted spatial patterning of the olfactory epithelium, without disrupting the one-receptor-type-per-cell rule. Tex15 encodes a transcriptional repressor ⁵ , and we show that Tex15-/- mice have reduced heterochromatin-associated H3K9me3 on OR genes. Thus, we propose that Tex15 directs a heterochromatin-based transcriptional repression mechanism that prevents uneven transcriptional onset from skewing OR choice. This mechanism safeguards the cellular diversity that is essential for broadly tuned chemosensation.