Mir322-KO Mouse

Mir322, orthologous to human miR-424, is a microRNA that plays significant roles in multiple biological processes. It is involved in pathways such as angiogenesis, cell apoptosis, and differentiation, which are crucial for normal development and disease-related responses. Genetic models, especially mouse models, have been valuable in studying its functions [1-10].

In a LacZ-tagged miR322 cluster reporter mouse model, vascular endothelial cells were identified as the major cellular source of the miR322 cluster in adult hearts. Intramyocardial injection of mimic-miR322 in an ischemia/reperfusion (MI/R) mouse model significantly diminished cardiac apoptosis and reduced infarct size, suggesting its cardioprotective effect. FBXW7, an ubiquitin ligase for activated Notch1 turnover, was identified as a direct target of miR322 in this context [1]. In Zswim8-null mouse embryos, deletion of miR-322 and miR-503 rescued growth, indicating their role in regulating mammalian body size through the target-directed microRNA degradation (TDMD) pathway [2]. In a mouse model of diabetic pregnancy, overexpression of miR-322 in embryos reduced neural tube defects, with IRE1α identified as an endonuclease that degrades precursor miR-322 [3]. In streptozotocin-induced diabetic mice, miR-322 was found to be involved in regulating chondrocyte proliferation and differentiation in the offspring's growth plate [4]. In Hdac3 knockout mouse epicardial cells, upregulation of miR-322 and miR-503 repressed FGF9 and IGF2 expression, affecting myocardial growth [5]. In mESCs transfected with lentivirus-mediated miR-322, miR-322 promoted the differentiation of embryonic stem cells into cardiomyocytes [6]. In a rat model of myocardial ischemia/reperfusion injury, overexpression of miR-322 suppressed cell injury [7]. In a mouse model with cartilage-specific deletion of the Mirc24 cluster containing miR-322, an increased level of miR-322 raised Rankl gene expression, affecting bone remodeling [8]. In adipocyte precursors, miR-322 was upregulated upon IL-4 stimulation and regulated cell proliferation to facilitate differentiation [9]. In mice with endothelial-specific deletion of miR-322 and miR-503, there was an augmented angiogenic response to LPS, suggesting their role in regulating inflammation-mediated angiogenesis [10].

In conclusion, Mir322 is involved in diverse biological functions such as cardiac protection during ischemia/reperfusion, embryonic growth regulation, prevention of neural tube defects in diabetic pregnancies, regulation of chondrocyte behavior in gestational diabetes, myocardial growth, stem cell differentiation, and modulation of angiogenesis. The use of gene knockout and other genetic mouse models has been instrumental in revealing its functions in these disease-relevant biological processes, providing potential therapeutic targets for related diseases.

References:

1. Chen, Zixin, Su, Xuan, Shen, Yan, Weintraub, Neal L, Tang, Yaoliang. 2019. MiR322 mediates cardioprotection against ischemia/reperfusion injury via FBXW7/notch pathway. In Journal of molecular and cellular cardiology, 133, 67-74. doi:10.1016/j.yjmcc.2019.05.020. https://pubmed.ncbi.nlm.nih.gov/31150734/

2. Jones, Benjamin T, Han, Jaeil, Zhang, He, Acharya, Asha, Mendell, Joshua T. 2023. Target-directed microRNA degradation regulates developmental microRNA expression and embryonic growth in mammals. In Genes & development, 37, 661-674. doi:10.1101/gad.350906.123. https://pubmed.ncbi.nlm.nih.gov/37553261/

3. Wang, Guanglei, Song, Shicong, Shen, Wei-Bin, Reece, E Albert, Yang, Peixin. 2023. MicroRNA-322 overexpression reduces neural tube defects in diabetic pregnancies. In American journal of obstetrics and gynecology, 230, 254.e1-254.e13. doi:10.1016/j.ajog.2023.07.048. https://pubmed.ncbi.nlm.nih.gov/37531989/

4. Qian, Fan, Chen, Xianlong, Wang, Simiao, Yang, Xuesong, Cheng, Xin. 2024. MiR-322-5p is involved in regulating chondrocyte proliferation and differentiation in offspring's growth plate of maternal gestational diabetes. In Scientific reports, 14, 20136. doi:10.1038/s41598-024-69523-z. https://pubmed.ncbi.nlm.nih.gov/39209899/

5. Jang, Jihyun, Song, Guang, Pettit, Sarah M, Kaushal, Sunjay, Li, Deqiang. 2022. Epicardial HDAC3 Promotes Myocardial Growth Through a Novel MicroRNA Pathway. In Circulation research, 131, 151-164. doi:10.1161/CIRCRESAHA.122.320785. https://pubmed.ncbi.nlm.nih.gov/35722872/

6. Liu, Kai, Peng, Xiaoping, Luo, Liang. 2023. miR-322 promotes the differentiation of embryonic stem cells into cardiomyocytes. In Functional & integrative genomics, 23, 87. doi:10.1007/s10142-023-01008-0. https://pubmed.ncbi.nlm.nih.gov/36932296/

7. Dong, Wei, Weng, Jun-Fei, Zhu, Jian-Bing, Peng, Xiao-Ping, Chen, Xuan-Ying. . CREB-binding protein and HIF-1α/β-catenin to upregulate miR-322 and alleviate myocardial ischemia-reperfusion injury. In FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 37, e22996. doi:10.1096/fj.202200596RRRRRR. https://pubmed.ncbi.nlm.nih.gov/37566526/

8. Georgieva, Veronika S, Bluhm, Björn, Probst, Kristina, Niehoff, Anja, Brachvogel, Bent. 2022. Ablation of the miRNA cluster 24 in cartilage and osteoblasts impairs bone remodeling. In Scientific reports, 12, 9116. doi:10.1038/s41598-022-13231-z. https://pubmed.ncbi.nlm.nih.gov/35650319/

9. Munkhzul, Choijamts, Lee, Ji-Min, Kim, Boseon, Lee, Min-Woo, Lee, Mihye. 2023. H19X-encoded microRNAs induced by IL-4 in adipocyte precursors regulate proliferation to facilitate differentiation. In Biology direct, 18, 32. doi:10.1186/s13062-023-00388-4. https://pubmed.ncbi.nlm.nih.gov/37322541/

10. Lee, Aram, Papangeli, Irinna, Park, Youngsook, Kim, Jongmin, Chun, Hyung J. 2017. A PPARγ-dependent miR-424/503-CD40 axis regulates inflammation mediated angiogenesis. In Scientific reports, 7, 2528. doi:10.1038/s41598-017-02852-4. https://pubmed.ncbi.nlm.nih.gov/28566713/