The microRNA/TET3/REST axis is required for olfactory globose basal cell proliferation and male behavior.

In the main olfactory epithelium (MOE), new olfactory sensory neurons (OSNs) are persistently generated to replace lost neurons throughout an organism's lifespan. This process predominantly depends on the proliferation of globose basal cells (GBCs), the actively dividing stem cells in the MOE. Here, by using CRISPR/Cas9 and RNAi coupled with adeno-associated virus (AAV) nose delivery approaches, we demonstrated that knockdown of miR-200b/a in the MOE resulted in supernumerary Mash1-marked GBCs and decreased numbers of differentiated OSNs, accompanied by abrogation of male behaviors. We further showed that in the MOE, miR-200b/a targets the ten-eleven translocation methylcytosine dioxygenase TET3, which cooperates with RE1-silencing transcription factor (REST) to exert their functions. Deficiencies including proliferation, differentiation, and behaviors illustrated in miR-200b/a knockdown mice were rescued by suppressing either TET3 or REST. Our work describes a mechanism of coordination of GBC proliferation and differentiation in the MOE and olfactory male behaviors through miR-200/TET3/REST signaling.