Gli3, also known as Glioma-associated oncogene homolog 3, is a transcription factor that is a key member of the Hedgehog (Hh/HH) signaling pathway [1]. It exists in two forms: a full-length (Gli3-FL) form that can regulate HH genes by targeting the GLI1 promoter in response to HH activation, and a repressor (Gli3-R) form generated through phosphorylation-mediated partial degradation in the absence of HH signaling [1]. GLI3 is crucial for tissue development, immune cell development, and has implications in cancer, making it a molecule of great biological importance [1]. Genetic models, such as KO/CKO mouse models, are valuable in studying its functions.

In mice, the absence of Gli3 impairs brain and lung development [1]. In skeletal muscle, satellite cells lacking GLI3 enter the GAlert state without injury and show enhanced self-renewal and regenerative capacity, as GLI3 is required to maintain satellite cells in a G0 dormant state [2]. In Pallister-Hall syndrome (PHS), a truncating variant in the middle third of the GLI3 gene leads to a variety of clinical phenotypes including congenital anomalies of the kidney and urinary tract (CAKUT) [3].

In conclusion, Gli3 is essential for multiple biological processes, with its functions in development and disease being revealed through model-based research. The study of Gli3 KO/CKO mouse models has contributed to understanding its role in diseases like PHS and its impact on organ development [1,2,3].

References:

1. Matissek, Stephan J, Elsawa, Sherine F. 2020. GLI3: a mediator of genetic diseases, development and cancer. In Cell communication and signaling : CCS, 18, 54. doi:10.1186/s12964-020-00540-x. https://pubmed.ncbi.nlm.nih.gov/32245491/

2. Brun, Caroline E, Sincennes, Marie-Claude, Lin, Alexander Y T, Le Grand, Fabien, Rudnicki, Michael A. 2022. GLI3 regulates muscle stem cell entry into GAlert and self-renewal. In Nature communications, 13, 3961. doi:10.1038/s41467-022-31695-5. https://pubmed.ncbi.nlm.nih.gov/35803939/

3. McClelland, Kathryn, Li, Weili, Rosenblum, Norman D. 2022. Pallister-Hall syndrome, GLI3, and kidney malformation. In American journal of medical genetics. Part C, Seminars in medical genetics, 190, 264-278. doi:10.1002/ajmg.c.31999. https://pubmed.ncbi.nlm.nih.gov/36165461/