Dhx15-KO Mouse

Dhx15, also known as DEAH-box helicase 15, is an ATP-dependent RNA helicase. It is mainly involved in RNA metabolism, including RNA splicing and ribosome maturation [4]. It is associated with multiple pathways such as the Wnt signaling pathway, which is crucial for various developmental processes [1]. Dhx15 is of great biological importance as it participates in numerous biological processes related to development and disease. Genetic models like zebrafish and mice are valuable for studying Dhx15.

In zebrafish, dhx15 knockout leads to profound intestinal defects, with decreased intestinal cell proliferation and increased apoptosis. The Wnt signaling pathway is down-regulated in these knockout zebrafish, indicating that dhx15 regulates zebrafish intestinal development through this pathway [1]. In T-cell acute lymphoblastic leukemia (T-ALL) murine models, DHX15 is identified as a dependency factor. Its depletion hinders burst proliferation during T-cell development, perturbs RNA splicing, and suppresses glutamine import and mTORC1 activity [2]. In Villin-Cre/KrasG12D+/- mice, knockout of Dhx15 attenuates the colorectal cancer (CRC) phenotype as Fusobacterium nucleatum promotes CRC progression by binding to DHX15 [3]. IEC-specific Dhx15-knockout mice show impaired IFN-β, IFN-λ3, and IL-18 production in response to enteric RNA viruses, resulting in uncontrolled intestinal inflammation [5]. In zebrafish, dhx15 -/- leads to perturbed hematopoietic stem/progenitor cells, with inhibited proliferation mediated through the unfolded protein response (UPR) pathway [6]. Homozygous Dhx15 gene deficiency is lethal in zebrafish and mouse embryos. In mice, it impairs liver organogenesis in embryos and liver regeneration after partial hepatectomy, and also affects liver metastasis and primary tumor growth in hepatocellular carcinoma models [7].

In conclusion, Dhx15 plays essential roles in multiple biological processes such as intestinal development, hematopoiesis, and liver development and regeneration. Through gene knockout models in zebrafish and mice, its significance in diseases like leukemia, CRC, and liver cancer has been revealed. These studies contribute to understanding the molecular mechanisms underlying these diseases and may provide potential therapeutic targets.

References:

1. Yao, Jinpeng, Cai, Yuanhua, Chen, Zhixiang, Li, Yang, Wang, Shaoyuan. 2023. Dhx15 regulates zebrafish intestinal development through the Wnt signaling pathway. In Genomics, 115, 110578. doi:10.1016/j.ygeno.2023.110578. https://pubmed.ncbi.nlm.nih.gov/36775210/

2. Guo, Hao, Xu, Jin, Xing, Peiqi, Van Vlierberghe, Pieter, Liu, Hudan. 2023. RNA helicase DHX15 exemplifies a unique dependency in acute leukemia. In Haematologica, 108, 2029-2043. doi:10.3324/haematol.2022.282066. https://pubmed.ncbi.nlm.nih.gov/36861414/

3. Zhu, Huiyuan, Li, Man, Bi, Dexi, Wei, Qing, Qin, Huanlong. 2024. Fusobacterium nucleatum promotes tumor progression in KRAS p.G12D-mutant colorectal cancer by binding to DHX15. In Nature communications, 15, 1688. doi:10.1038/s41467-024-45572-w. https://pubmed.ncbi.nlm.nih.gov/38402201/

4. Zhao, Miaomiao, Ying, Lixiong, Wang, Rusha, Chen, Zhi, Yang, Zhenggang. 2021. DHX15 Inhibits Autophagy and the Proliferation of Hepatoma Cells. In Frontiers in medicine, 7, 591736. doi:10.3389/fmed.2020.591736. https://pubmed.ncbi.nlm.nih.gov/33644083/

5. Xing, Junji, Zhou, Xiaojing, Fang, Mingli, Minze, Laurie J, Zhang, Zhiqiang. . DHX15 is required to control RNA virus-induced intestinal inflammation. In Cell reports, 35, 109205. doi:10.1016/j.celrep.2021.109205. https://pubmed.ncbi.nlm.nih.gov/34161762/

6. Cai, Yuanhua, Wang, Jing, Jin, Daqing, Zhong, Tao Peter, Wang, Shaoyuan. 2021. Dhx15 regulates zebrafish definitive hematopoiesis through the unfolded protein response pathway. In Cancer science, 112, 3884-3894. doi:10.1111/cas.15002. https://pubmed.ncbi.nlm.nih.gov/34077586/

7. Portolés, Irene, Ribera, Jordi, Fernandez-Galán, Esther, Jiménez, Wladimiro, Morales-Ruiz, Manuel. 2024. Identification of Dhx15 as a Major Regulator of Liver Development, Regeneration, and Tumor Growth in Zebrafish and Mice. In International journal of molecular sciences, 25, . doi:10.3390/ijms25073716. https://pubmed.ncbi.nlm.nih.gov/38612527/