Related Experiment Video
Updated: Jul 14, 2025
Author Spotlight: Exploring Microglial Interactions with Stress-Response Circuitry Using the Limited Bedding and Nesting Model
Published on: July 12, 2024
miR-377-3p Regulates Hippocampal Neurogenesis via the Zfp462-Pbx1 Pathway and Mediates Anxiety-Like Behaviors in
Bin Wang1, Yichen Zhu2, Bin Wei3
1Institute for Fetology, The First Affiliated Hospital of Soochow University, Suzhou City, 215006, Jiangsu, China. binwang2233@suda.edu.cn.
Insights
Prenatal hypoxia (PH) causes anxiety-like behaviors by increasing miR-377-3p, which downregulates Zfp462 and the Akt-GSK3β-CREB pathway, impairing hippocampal neurogenesis. Restoring Zfp462 expression alleviates these effects.
Area of Science:
- Neuroscience
- Developmental Biology
- Molecular Biology
Background:
- Prenatal hypoxia (PH) is a common obstetric complication linked to neurological disorders, including anxiety.
- Previous studies identified anxiety-like behavior in Zfp462 heterozygous mice and PH offspring, with reduced Zfp462 and increased miR-377-3p in PH mice.
- The precise molecular mechanisms linking PH, Zfp462, miR-377-3p, and anxiety remain unclear.
Purpose of the Study:
- To elucidate the regulatory mechanisms of the miR-377-3p-Zfp462-Pbx1 pathway in the brains of prenatal hypoxic offspring.
- To investigate the role of this pathway in the pathogenesis of anxiety-like behaviors.
- To assess the therapeutic potential of targeting miR-377-3p for anxiety in PH offspring.
Main Methods:
- Utilized western blotting, gene knockdown, immunofluorescence, dual-luciferase reporter assay, immunoprecipitation, and quantitative real-time PCR.
- Employed cell transfection with miR-377-3p mimics or inhibitors and rescue assays.
- Administered miR-377-3p antagomir via microinjection into the hippocampal dentate gyrus of PH mice.
Main Results:
- Zfp462 deficiency promoted Pbx1 protein degradation via ubiquitination.
- PH mice exhibited increased miR-377-3p, decreased Zfp462/Pbx1-Akt-GSK3β-CREB pathway activity, reduced hippocampal neurogenesis, and anxiety-like behaviors.
- miR-377-3p directly targets Zfp462 mRNA; antagomir treatment improved pathway activity, neurogenesis, and anxiety behaviors in PH mice.
Conclusions:
- miR-377-3p plays a critical role in regulating hippocampal neurogenesis and anxiety-like behaviors in prenatal hypoxic offspring.
- The miR-377-3p-Zfp462-Pbx1-Akt-GSK3β-CREB pathway is a key mediator of these effects.
- miR-377-3p represents a potential therapeutic target for anxiety associated with prenatal hypoxia.
Abstract:
Prenatal hypoxia (PH) is one of the most common complications of obstetrics and is closely associated with many neurological disorders such as depression, anxiety, and cognitive impairment. Our previous study found that Zfp462 heterozygous (Het) mice exhibit significant anxiety-like behavior. Interestingly, offspring mice with PH also have anxiety-like behaviors in adulthood, accompanied by reduced expression of Zfp462 and increased expression of miR-377-3p; however, the exact regulatory mechanisms remain unclear. In this study, western blotting, gene knockdown, immunofluorescence, dual-luciferase reporter assay, immunoprecipitation, cell transfection with miR-377-3p mimics or inhibitors, quantitative real-time PCR, and rescue assay were used to detect changes in the miR-377-3p-Zfp462-Pbx1 (pre-B-cell leukemia homeobox1) pathway in the brains of prenatal hypoxic offspring to explain the pathogenesis of anxiety-like behaviors. We found that Zfp462 deficiency promoted Pbx1 protein degradation through ubiquitination and that Zfp462 Het mice showed downregulation of the protein kinase B (PKB, also called Akt)-glycogen synthase kinase-3β (GSK3β)-cAMP response element-binding protein (CREB) pathway and hippocampal neurogenesis with anxiety-like behavior. In addition, PH mice exhibited upregulation of miR-377-3p, downregulation of Zfp462/Pbx1-Akt-GSK3β-CREB pathway activity, reduced hippocampal neurogenesis, and an anxiety-like phenotype. Intriguingly, miR-377-3p directly targets the 3'UTR of Zfp462 mRNA to regulate Zfp462 expression. Importantly, microinjection of miR-377-3p antagomir into the hippocampal dentate gyrus of PH mice upregulated Zfp462/Pbx1-Akt-GSK3β-CREB pathway activity, increased hippocampal neurogenesis, and improved anxiety-like behaviors. Collectively, our findings demonstrated a crucial role for miR-377-3p in the regulation of hippocampal neurogenesis and anxiety-like behaviors via the Zfp462/Pbx1-Akt-GSK3β-CREB pathway. Therefore, miR-377-3p could be a potential therapeutic target for anxiety-like behavior in prenatal hypoxic offspring.
More Related Videos
07:43Immunohistochemical Visualization of Hippocampal Neuron Activity After Spatial Learning in a Mouse Model of Neurodevelopmental Disorders
Published on: May 12, 2015
09:06Stereotactic Injection of MicroRNA-expressing Lentiviruses to the Mouse Hippocampus CA1 Region and Assessment of the Behavioral Outcome
Published on: June 10, 2013