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 theMOE. Here, by usingCRISPR/Cas9 andRNAi coupled with adeno-associated virus (AAV) nose delivery approaches, we demonstrated that knockdown of miR-200b/a in theMOEresulted in supernumerary Mash1-markedGBCs and decreased numbers of differentiatedOSNs, accompanied by abrogation of male behaviors. We further showed that in theMOE, miR-200b/a targets the ten-eleven translocation methylcytosine dioxygenaseTET3, which cooperates withRE1-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 eitherTET3 orREST. Our work describes a mechanism of coordination ofGBCproliferation and differentiation in theMOEand olfactory male behaviors through miR-200/TET3/RESTsignaling.