Mis12-KO Mouse

Mis12 is a gene encoding a protein that plays significant roles in multiple biological processes. It is part of the Mis12 complex which is crucial for kinetochore function, a key structure linking chromosomes to spindle microtubules for accurate chromosome segregation during mitosis and meiosis [3,5,6,7]. This complex also participates in regulatory pathways related to cell cycle transitions and cellular senescence. Genetic models, such as knockout (KO) or conditional knockout (CKO) mouse models, are valuable tools for studying Mis12's functions.

In mouse oocytes, Mis12 depletion severely compromised germinal vesicle breakdown (GVBD) by impairing cyclin B1 accumulation, highlighting its essential role in meiotic G2/M transition. However, Mis12 was dispensable for meiotic progression through meiosis I and II [1]. In human mesenchymal stem cells (hMSCs), knockout of METTL3, which normally stabilizes MIS12 mRNA through m6A modification, accelerated cellular senescence, indicating that Mis12 is important in preventing premature aging [2]. In atherosclerotic plaque, downregulation of FTO, which stabilizes the MIS12 protein, led to increased vascular smooth muscle cell (VSMC) senescence, suggesting Mis12's role in inhibiting VSMC senescence and atherosclerotic plaque progression [4].

In conclusion, Mis12 is essential for processes like chromosome segregation during cell division, meiotic G2/M transition, and prevention of cellular senescence. Mouse KO/CKO models have contributed to understanding its role in diseases related to abnormal cell cycle regulation and premature aging, such as those associated with meiotic defects and atherosclerotic plaque development.

References:

1. Bai, Guang-Yu, Choe, Min Ho, Kim, Jae-Sung, Oh, Jeong Su. 2020. Mis12 controls cyclin B1 stabilization via Cdc14B-mediated APC/CCdh1 regulation during meiotic G2/M transition in mouse oocytes. In Development (Cambridge, England), 147, . doi:10.1242/dev.185322. https://pubmed.ncbi.nlm.nih.gov/32341029/

2. Wu, Zeming, Shi, Yue, Lu, Mingming, Ci, Weimin, Qu, Jing. . METTL3 counteracts premature aging via m6A-dependent stabilization of MIS12 mRNA. In Nucleic acids research, 48, 11083-11096. doi:10.1093/nar/gkaa816. https://pubmed.ncbi.nlm.nih.gov/33035345/

3. Ladurner, Rene, Straight, Aaron F. . MIS12/MIND Control at the Kinetochore. In Cell, 167, 889-891. doi:10.1016/j.cell.2016.10.036. https://pubmed.ncbi.nlm.nih.gov/27814517/

4. Sun, Jingzhao, Wang, Mengqi, Jia, Fengming, Ren, Jinlin, Hu, Bo. 2024. FTO Stabilizes MIS12 to Inhibit Vascular Smooth Muscle Cell Senescence in Atherosclerotic Plaque. In Journal of inflammation research, 17, 1857-1871. doi:10.2147/JIR.S447379. https://pubmed.ncbi.nlm.nih.gov/38523689/

5. Petrovic, Arsen, Pasqualato, Sebastiano, Dube, Prakash, Stark, Holger, Musacchio, Andrea. . The MIS12 complex is a protein interaction hub for outer kinetochore assembly. In The Journal of cell biology, 190, 835-52. doi:10.1083/jcb.201002070. https://pubmed.ncbi.nlm.nih.gov/20819937/

6. Petrovic, Arsen, Keller, Jenny, Liu, Yahui, Vetter, Ingrid R, Musacchio, Andrea. 2016. Structure of the MIS12 Complex and Molecular Basis of Its Interaction with CENP-C at Human Kinetochores. In Cell, 167, 1028-1040.e15. doi:10.1016/j.cell.2016.10.005. https://pubmed.ncbi.nlm.nih.gov/27881301/

7. Venkei, Zsolt, Przewloka, Marcin R, Glover, David M. 2010. Drosophila Mis12 complex acts as a single functional unit essential for anaphase chromosome movement and a robust spindle assembly checkpoint. In Genetics, 187, 131-40. doi:10.1534/genetics.110.119628. https://pubmed.ncbi.nlm.nih.gov/20980244/