Gli1, short for Glioma-associated oncogene 1, is a transcriptional effector at the terminal end of the Hedgehog signaling (Hh) pathway. It is tightly regulated during embryonic development, tissue patterning, and differentiation. The Hh pathway, in which Gli1 is a key component, is crucial for normal development and tissue homeostasis [3].

In the context of diseases, Gli1-altered mesenchymal tumors, characterized by fusions or amplifications of GLI1, have been reported. These tumors can metastasize and are best considered sarcomas [1]. In non-small cell lung cancer, Gli1-mediated tumor cell-derived bFGF promotes tumor angiogenesis and pericyte coverage [5]. In triple-negative breast cancer, curcumin inhibits invasion and metastasis via the Hedgehog/Gli1 signaling pathway [6]. In rheumatoid arthritis, GLI1 in synovial tissue is positively correlated with RA-related scores, and its inhibition alleviates joint inflammation and bone destruction in collagen-induced arthritis mouse models by regulating macrophage M1 polarization and osteoclast activation [8]. In muscle regeneration, Gli1+ muscle stem cells (MuSCs) are more active in homeostatic muscle and rapidly respond to injury to initiate muscle regeneration [7]. In periodontium, Gli1+ cells are multipotential stem cells regulated by osteocytes and occlusal force [2]. In condylar development and temporomandibular joint osteoarthritis (TMJOA), β-catenin orchestrates Gli1+ cell fate [4].

In conclusion, Gli1 is essential for the regulation of multiple biological processes and is implicated in various disease conditions, including tumorigenesis, angiogenesis, and joint-related diseases. Studies using models such as gene-modified mouse models have significantly enhanced our understanding of Gli1's functions, offering potential therapeutic targets for associated diseases.

References:

1. Cloutier, Jeffrey M, Kerr, Darcy A. 2023. GLI1-Altered Mesenchymal Tumors. In Surgical pathology clinics, 17, 13-24. doi:10.1016/j.path.2023.06.004. https://pubmed.ncbi.nlm.nih.gov/38278602/

2. Men, Yi, Wang, Yuhong, Yi, Yating, Feng, Jian Q, Zhao, Hu. 2020. Gli1+ Periodontium Stem Cells Are Regulated by Osteocytes and Occlusal Force. In Developmental cell, 54, 639-654.e6. doi:10.1016/j.devcel.2020.06.006. https://pubmed.ncbi.nlm.nih.gov/32652075/

3. Avery, Justin T, Zhang, Ruowen, Boohaker, Rebecca J. 2021. GLI1: A Therapeutic Target for Cancer. In Frontiers in oncology, 11, 673154. doi:10.3389/fonc.2021.673154. https://pubmed.ncbi.nlm.nih.gov/34113570/

4. Wang, J, Dong, X, Lei, J, Chen, S, He, Y. 2024. β-catenin Orchestrates Gli1+ Cell Fate in Condylar Development and TMJOA. In Journal of dental research, 103, 1291-1301. doi:10.1177/00220345241274354. https://pubmed.ncbi.nlm.nih.gov/39400124/

5. Lei, Xueping, Li, Zhan, Huang, Manting, Liu, Junshan, Yu, Xiyong. 2024. Gli1-mediated tumor cell-derived bFGF promotes tumor angiogenesis and pericyte coverage in non-small cell lung cancer. In Journal of experimental & clinical cancer research : CR, 43, 83. doi:10.1186/s13046-024-03003-0. https://pubmed.ncbi.nlm.nih.gov/38493151/

6. Li, Mengjie, Guo, Tingting, Lin, Jiayi, Fang, Chunping, Hu, Chenxia. 2021. Curcumin inhibits the invasion and metastasis of triple negative breast cancer via Hedgehog/Gli1 signaling pathway. In Journal of ethnopharmacology, 283, 114689. doi:10.1016/j.jep.2021.114689. https://pubmed.ncbi.nlm.nih.gov/34592340/

7. Peng, Jiayin, Han, Lili, Liu, Biao, Hu, Ping, Zhao, Yun. 2023. Gli1 marks a sentinel muscle stem cell population for muscle regeneration. In Nature communications, 14, 6993. doi:10.1038/s41467-023-42837-8. https://pubmed.ncbi.nlm.nih.gov/37914731/

8. Ge, Gaoran, Guo, Qianping, Zhou, Ying, Li, Bin, Geng, Dechun. 2023. GLI1 facilitates collagen-induced arthritis in mice by collaborative regulation of DNA methyltransferases. In eLife, 12, . doi:10.7554/eLife.92142. https://pubmed.ncbi.nlm.nih.gov/37929702/