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The microRNA-29ab1/Zfp36/AR Axis in the Hypothalamus Regulates Male-Typical Behaviors in Mice
Jie Ma1, Yingying Lin2, Wei Xiong2
1College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China.
Abstract:
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 miR-29, play a vital role in reproduction and the neural control of behaviors. However, it remains unclear whether miR-29 affects reproduction through the hypothalamus-mediated regulation of male-typical behaviors. Here, we constructed two mouse knockout models by ablating either the miR-29ab1 or miR-29b2c cluster. Compared to WT, the ablation of miR-29ab1 in male mice significantly reduced the incidence of aggression by 60% and the incidence of mating by 46.15%. Furthermore, the loss of miR-29ab1 in male mice led to the downregulation of androgen receptor (AR) in the ventromedial hypothalamus. Transcriptomic analysis of the hypothalamus of miR-29ab1-deficient mice revealed inflammatory activation and aberrant expression of genes associated with male-typical behaviors, including Ar, Pgr, Htr4, and Htr2c. Using bioinformatics analysis and dual-luciferase reporter assays, we identified zinc finger protein 36 (Zfp36) as a direct downstream target gene of miR-29ab1. We subsequently showed that ZFP36 colocalized with AR in GT1-7 cells. Furthermore, inhibition of Zfp36 or RelB in GT1-7 cells led to an increase in AR expression. Collectively, our results demonstrate that the miR-29ab1/Zfp36/AR 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.
Insights
MicroRNA miR-29ab1 regulates male aggression and mating behaviors via the hypothalamus. Its absence reduces these behaviors and impacts androgen receptor signaling, offering potential therapeutic targets for low libido.
Area of Science:
- Neuroendocrinology
- Molecular Biology
- Behavioral Neuroscience
Background:
- Male-typical behaviors like aggression and mating are regulated by the hypothalamus.
- MicroRNAs (miRNAs), particularly miR-29, are implicated in reproduction and neural control.
- The specific role of miR-29 in hypothalamus-mediated male behaviors remains unclear.
Purpose of the Study:
- To investigate the role of miR-29 in regulating male-typical behaviors through hypothalamic pathways.
- To elucidate the molecular mechanisms underlying miR-29's influence on aggression and mating.
Main Methods:
- Construction of miR-29ab1 and miR-29b2c knockout mouse models.
- Behavioral analysis of aggression and mating incidence.
- Hypothalamic gene expression profiling (transcriptomics) and protein analysis (Western blotting, immunohistochemistry).
- Bioinformatics analysis and dual-luciferase reporter assays to identify miRNA targets.
- Cellular experiments (GT1-7 cells) to validate molecular interactions.
Main Results:
- Ablation of miR-29ab1 significantly reduced male mouse aggression (60%) and mating (46.15%).
- Loss of miR-29ab1 led to downregulation of androgen receptor (AR) in the ventromedial hypothalamus.
- Transcriptomic analysis revealed inflammatory activation and altered expression of key genes (Ar, Pgr, Htr4, Htr2c) in knockout mice.
- Zinc finger protein 36 (Zfp36) was identified as a direct downstream target of miR-29ab1.
- ZFP36 and AR colocalized, and inhibition of Zfp36 or RelB increased AR expression in GT1-7 cells.
Conclusions:
- The miR-29ab1/Zfp36/AR axis in the hypothalamus is crucial for regulating male aggression and mating behaviors.
- This pathway provides a potential therapeutic target for infertility associated with low libido.
