Axin2, also known as Conductin, is a key inhibitory molecule in the Wnt signaling pathway [1,2,3,4,6]. The Wnt pathway is crucial for many biological processes such as cell proliferation, differentiation, and tissue homeostasis [1,2,3,4,5,6]. Axin2 plays a vital role in maintaining the balance of Wnt signaling, which is essential for normal development and physiological functions [1,2,3,4,6]. Genetic models, like KO or CKO mouse models, are valuable tools for studying Axin2's functions.

In ASD mouse models (Shank3-/- and valproic acid-treated mice), aberrant Wnt signaling activation was observed, and Axin2 interacted with the glycolytic enzyme ENO1 in ASD neurons. An Axin2 stabilizer, XAV939, blocked this interaction, rescued synaptic and social phenotypes, indicating Axin2 as a potential therapeutic target for social dysfunction in ASD [1]. In colorectal cancer, ALKBH5 binds and demethylates Axin2 mRNA, leading to its degradation and hyperactivation of the Wnt/β-catenin pathway, promoting tumorigenesis and immunosuppression. Targeting ALKBH5 could be a strategy for immunotherapy [2]. CDX2 inhibits colon cancer cell proliferation by suppressing Wnt/β-catenin signaling via transactivation of Axin2 expression [3]. In CRC, a small-molecule compound CW85319 enhances Axin2 degradation, suppressing CRC growth and metastasis [4]. In a macrophage Axin2 cKO mouse model, Axin2 depletion alleviated senescence and increased immune response after myocardial infarction [7].

In conclusion, Axin2 is essential for regulating Wnt signaling, which impacts various biological processes and disease conditions. The study of Axin2 using KO/CKO mouse models has revealed its significance in ASD, colorectal cancer, and post-myocardial infarction recovery, providing potential therapeutic directions for these diseases.

References:

1. Wang, Mengmeng, Xian, Panpan, Zheng, Weian, Wang, Yazhou, Wu, Shengxi. 2023. Axin2 coupled excessive Wnt-glycolysis signaling mediates social defect in autism spectrum disorders. In EMBO molecular medicine, 15, e17101. doi:10.15252/emmm.202217101. https://pubmed.ncbi.nlm.nih.gov/37078424/

2. Zhai, Jianning, Chen, Huarong, Wong, Chi Chun, Sung, Joseph Jao-Yiu, Yu, Jun. 2023. ALKBH5 Drives Immune Suppression Via Targeting AXIN2 to Promote Colorectal Cancer and Is a Target for Boosting Immunotherapy. In Gastroenterology, 165, 445-462. doi:10.1053/j.gastro.2023.04.032. https://pubmed.ncbi.nlm.nih.gov/37169182/

3. Yu, Junhui, Liu, Dong, Sun, Xuejun, Wang, Chunbao, Zheng, Jianbao. 2019. CDX2 inhibits the proliferation and tumor formation of colon cancer cells by suppressing Wnt/β-catenin signaling via transactivation of GSK-3β and Axin2 expression. In Cell death & disease, 10, 26. doi:10.1038/s41419-018-1263-9. https://pubmed.ncbi.nlm.nih.gov/30631044/

4. Cheng, Li-Zhi, Huang, Dan-Ling, Tang, Zhang-Rui, Cheng, Yong-Xian, Wu, Zhao-Qiu. 2023. Pharmacological targeting of Axin2 suppresses cell growth and metastasis in colorectal cancer. In British journal of pharmacology, 180, 3071-3091. doi:10.1111/bph.16193. https://pubmed.ncbi.nlm.nih.gov/37461816/

5. Walia, B, Li, T M, Crosio, G, Montero, A M, Huang, A H. 2022. Axin2-lineage cells contribute to neonatal tendon regeneration. In Connective tissue research, 63, 530-543. doi:10.1080/03008207.2022.2036732. https://pubmed.ncbi.nlm.nih.gov/35180018/

6. de Roo, Jolanda J D, Chhatta, Amiet, Garcia-Perez, Laura, Mikkers, Harald, Staal, Frank J T. 2022. Axin2/Conductin Is Required for Normal Haematopoiesis and T Lymphopoiesis. In Cells, 11, . doi:10.3390/cells11172679. https://pubmed.ncbi.nlm.nih.gov/36078085/

7. Zheng, Yue, Wang, Yuchao, Qi, Bingcai, Liu, Yanwu, Li, Tong. 2023. Axin2 depletion in macrophages alleviated senescence and increased immune response after myocardial infarction. In Inflammation research : official journal of the European Histamine Research Society ... [et al.], 73, 407-414. doi:10.1007/s00011-023-01843-8. https://pubmed.ncbi.nlm.nih.gov/38158447/