Dclk1, or Doublecortin-like kinase 1, is a microtubule-associated protein kinase. It is involved in neurogenesis and has been associated with multiple pathways, including Notch, Wnt/β -catenin, and RAS, which are crucial in various biological processes [3,4]. It is also recognized as a stem cell marker in several tissues, and its abnormal expression is linked to human cancers, indicating its significant biological importance [3,4]. Genetic models, such as gene knockout (KO) or conditional knockout (CKO) mouse models, are valuable tools for studying its functions.

In atherosclerosis, macrophage-specific Dclk1 deletion in ApoE -/- mice fed a high-fat diet (HFD) attenuates the disease by reducing inflammation. Mechanistically, Dclk1 in macrophages binds to IKKβ, phosphorylates it at S177/181, and activates the NF-κB signaling pathway, promoting inflammatory gene expression [1]. In obesity-induced cardiomyopathy, macrophage-specific Dclk1 knockout, but not cardiomyocyte-specific knockout, prevents HFD-induced heart dysfunction, cardiac hypertrophy, and fibrosis. Dclk1 deficiency in macrophages suppresses RIP2/TAK1 activation and inflammatory responses [2].

In conclusion, Dclk1 plays a pro-inflammatory role in atherosclerosis and obesity-induced cardiomyopathy as revealed by macrophage-specific KO mouse models. These findings suggest Dclk1 as a potential therapeutic target for these inflammatory cardiovascular diseases, highlighting the importance of Dclk1 KO/CKO mouse models in understanding disease mechanisms and identifying novel treatment strategies [1,2].

References:

1. Huang, Zhuqi, Shen, Sirui, Han, Xue, Wu, Gaojun, Liang, Guang. 2023. Macrophage DCLK1 promotes atherosclerosis via binding to IKKβ and inducing inflammatory responses. In EMBO molecular medicine, 15, e17198. doi:10.15252/emmm.202217198. https://pubmed.ncbi.nlm.nih.gov/36896602/

2. Yang, Bin, Zhao, Yunjie, Luo, Wu, Wang, Yi, Liang, Guang. 2023. Macrophage DCLK1 promotes obesity-induced cardiomyopathy via activating RIP2/TAK1 signaling pathway. In Cell death & disease, 14, 419. doi:10.1038/s41419-023-05960-4. https://pubmed.ncbi.nlm.nih.gov/37443105/

3. Lu, Qin, Feng, Hailan, Chen, Hong, Yan, Zixing, Cao, Zhiyun. 2022. Role of DCLK1 in oncogenic signaling (Review). In International journal of oncology, 61, . doi:10.3892/ijo.2022.5427. https://pubmed.ncbi.nlm.nih.gov/36148883/

4. Ye, Liu, Liu, Beibei, Huang, Jingling, Xu, Yungen, Wang, Shuping. 2023. DCLK1 and its oncogenic functions: A promising therapeutic target for cancers. In Life sciences, 336, 122294. doi:10.1016/j.lfs.2023.122294. https://pubmed.ncbi.nlm.nih.gov/38007147/