The microRNA-29ab1/Zfp36/AR Axis in the Hypothalamus Regulates Male-Typical Behaviors in Mice.

Male-typical behaviors such as aggression and mating, which reflect sexual libido in male mice, are regulated by the hypothalamus, a crucial part of the nervous system. Previous studies have demonstrated that microRNAs (miRNAs), especially , play a vital role in reproduction and the neural control of behaviors. However, it remains unclear whether affects reproduction through the hypothalamus-mediated regulation of male-typical behaviors. Here, we constructed two mouse knockout models by ablating either the or cluster. Compared to WT, the ablation of in male mice significantly reduced the incidence of aggression by 60% and the incidence of mating by 46.15%. Furthermore, the loss of in male mice led to the downregulation of androgen receptor (AR) in the ventromedial hypothalamus. Transcriptomic analysis of the hypothalamus of -deficient mice revealed inflammatory activation and aberrant expression of genes associated with male-typical behaviors, including , , , and . Using bioinformatics analysis and dual-luciferase reporter assays, we identified zinc finger protein 36 () as a direct downstream target gene of . We subsequently showed that ZFP36 colocalized with AR in GT1-7 cells. Furthermore, inhibition of or in GT1-7 cells led to an increase in AR expression. Collectively, our results demonstrate that the axis in the hypothalamus plays a pivotal role in the regulation of aggression and mating in male mice, providing a potential therapeutic target for treating infertility caused by low libido.