Irx2, belonging to the Iroquois homeobox gene family, is a transcription factor. It plays roles in organ development, such as in the early lung development where it starts to express in the foregut region related to laryngo-tracheal groove formation, and is prominent in lung epithelium during glandular development [5]. It's also involved in hindlimb development, being coordinately expressed with Irx1 in interdigital tissue, digital primordia, etc., and regulated by retinoic acid, TGFβ and FGF signaling [6].

In disease-related studies, CF-specific Irx2-knockout mouse models show that deletion of Irx2 in cardiac fibroblasts protects against angiotensin II-induced pathological fibrotic remodelling and improves cardiac function in male mice, indicating that Irx2 drives cardiac fibrosis by transcriptionally activating EGR1 [1]. In osteosarcoma, knockdown of Irx2 with a lentivirus vector suppresses cell proliferation and invasion through the AKT/MMP9 signaling pathway, and EMP1 promotes the malignant progression of osteosarcoma through the IRX2/MMP9 axis [3,4]. In endometrial carcinoma, decreased expression of IRX2 facilitates cell growth through regulating RUVBL1 expression [2].

In conclusion, Irx2 is crucial in organ development and disease processes. Gene-knockout mouse models have been instrumental in revealing its role in cardiac fibrosis, osteosarcoma, and endometrial carcinoma, providing insights into disease mechanisms and potential therapeutic targets.

References:

1. Ma, Zhen-Guo, Yuan, Yu-Pei, Fan, Di, Wei, Wen-Ying, Tang, Qi-Zhu. 2023. IRX2 regulates angiotensin II-induced cardiac fibrosis by transcriptionally activating EGR1 in male mice. In Nature communications, 14, 4967. doi:10.1038/s41467-023-40639-6. https://pubmed.ncbi.nlm.nih.gov/37587150/

2. Xu, Qinyang, Zhou, Wanzhen, Zhou, Yuedi, Chen, Jing, Ma, Li. 2023. IRX2 regulates endometrial carcinoma oncogenesis by transcriptional repressing RUVBL1. In Experimental cell research, 434, 113866. doi:10.1016/j.yexcr.2023.113866. https://pubmed.ncbi.nlm.nih.gov/38042247/

3. Liu, Tielong, Zhou, Weiwei, Zhang, Fei, Xiao, Jianru, Wang, Yan. 2014. Knockdown of IRX2 inhibits osteosarcoma cell proliferation and invasion by the AKT/MMP9 signaling pathway. In Molecular medicine reports, 10, 169-74. doi:10.3892/mmr.2014.2215. https://pubmed.ncbi.nlm.nih.gov/24806332/

4. Wang, Mingfa, Liu, Tianyu, Hu, Xiaowei, Liu, Jingmin, Wang, Xiaoge. . EMP1 promotes the malignant progression of osteosarcoma through the IRX2/MMP9 axis. In Panminerva medica, 62, 150-154. doi:10.23736/S0031-0808.20.03913-0. https://pubmed.ncbi.nlm.nih.gov/32716150/

5. Becker, M B, Zülch, A, Bosse, A, Gruss, P. . Irx1 and Irx2 expression in early lung development. In Mechanisms of development, 106, 155-8. doi:. https://pubmed.ncbi.nlm.nih.gov/11472847/

6. Díaz-Hernández, Martha Elena, Bustamante, Marcia, Galván-Hernández, Claudio Iván, Chimal-Monroy, Jesús. 2013. Irx1 and Irx2 are coordinately expressed and regulated by retinoic acid, TGFβ and FGF signaling during chick hindlimb development. In PloS one, 8, e58549. doi:10.1371/journal.pone.0058549. https://pubmed.ncbi.nlm.nih.gov/23505533/