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miR-377-3p Regulates Hippocampal Neurogenesis via the Zfp462-Pbx1 Pathway and Mediates Anxiety-Like Behaviors in Prenatal Hypoxic Offspring

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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.

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Data Availability

All data generated or analyzed during this study are included in this published article.

Abbreviations

PH:

Prenatal hypoxia

Het:

Heterozygous

KO:

Knockout

FOAD:

Fetal origin adult diseases

Pbx1:

Pre-B-cell leukemia homeobox1

OFT:

Open field test

IP:

Immunoprecipitation

EPM:

Elevated plus maze

SDS:

Sodium dodecyl sulfate

ACSF:

Artificial cerebrospinal fluid

siRNA:

Small interfering RNA

PBS:

Phosphate-buffered saline

Akt/PKB:

Protein kinase B

GSK3β:

Glycogen synthase kinase-3β

CREB:

cAMP response element-binding protein

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Funding

This work was supported by grants from the National Natural Science Foundation of China (82101793, 81974244), Natural Science Foundation of Jiangsu Province (BK20210092), Suzhou Natural Science Foundation (SKJY2021061), and Suzhou city “Gu Su Wei Sheng Ren Cai” Research Project (GSWS2022010). We appreciate the support of the Jiangsu Innovative and Entrepreneurial Talent Programme (JSSCBS20211567) and the support of Suzhou city “Gu Su Wei Sheng Ren Cai” program (2021057).

Author information

Authors and Affiliations

  1. Institute for Fetology, The First Affiliated Hospital of Soochow University, Suzhou City, 215006, Jiangsu, China

    Bin Wang, Bin Wei, Hongtao Zeng, Pengjie Zhang, Lingjun Li & Miao Sun

  2. Cambridge-Suda Genomic Resource Center, Jiangsu Key Laboratory of Neuropsychiatric Diseases Research, Suzhou Medical College of Soochow University, Jiangsu, 215123, China

    Yichen Zhu

  3. Obstetrics and Gynecology Hospital Research Center, Institute of Reproduction and Development, Fudan University, Shanghai, 200433, China

    Hongyan Wang & Yufang Zheng

  4. State Key Laboratory of Genetic Engineering, MOE Key Laboratory of Contemporary Anthropology, and Collaborative Innovation Center for Genetics & Development, School of Life Sciences, Fudan University, Shanghai, 200438, China

    Hongyan Wang, Xiaohui Wu & Yufang Zheng

  5. Institute of Developmental Biology & Molecular Medicine, Fudan University, Shanghai, 200433, China

    Xiaohui Wu & Yufang Zheng

Authors
  1. Bin Wang
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  2. Yichen Zhu
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  3. Bin Wei
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  4. Hongtao Zeng
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  5. Pengjie Zhang
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  6. Lingjun Li
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  7. Hongyan Wang
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  8. Xiaohui Wu
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  9. Yufang Zheng
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  10. Miao Sun
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Corresponding authors

Correspondence to Bin Wang or Miao Sun.

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Ethics Approval and Consent to Participate

All animal experiments were carried out in accordance with the Laboratory Animal Management Regulations with approval of the Research Ethics Committee of the First Affiliated Hospital of Soochow University (No. 2020179).

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The authors declare no competing interests.

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Bin Wang and Yichen Zhu are co-first authors.

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Figure S1–S5 and Table S1 (DOCX 1397 kb)

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Wang, B., Zhu, Y., Wei, B. et al. miR-377-3p Regulates Hippocampal Neurogenesis via the Zfp462-Pbx1 Pathway and Mediates Anxiety-Like Behaviors in Prenatal Hypoxic Offspring. Mol Neurobiol 61, 1920–1935 (2024). https://doi.org/10.1007/s12035-023-03683-3

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