Gas1-KO Mouse

Gas1, or Growth Arrest Specific 1, is a gene with diverse functions. It is a member of the alpha receptors (GFRα) for the GDNF ligands (GFL) family and acts as a negative modulator of GDNF-induced intracellular signaling, leading to cell arrest and apoptosis [3]. It also interacts with Hh proteins to regulate the Hedgehog pathway, which is crucial in nervous system development and tumorigenesis [3]. Additionally, Gas1 may serve as an alternative receptor for GFLs due to its homology to GFR alpha [2].

In murine studies, Gas1 loss-of-function mutation leads to dental patterning defects. Mice with such mutations have variations in tooth number, morphology, and size within their molar dentition, including supernumerary teeth and cusp abnormalities. Gas1 in cranial neural crest cells restricts Wnt and downstream FGF signaling in odontogenic epithelium through Shh signal transduction [4]. In the context of colorectal cancer, Bifidobacterium adolescentis supplementation, which is correlated with increased Gas1 expression in CD143+ cancer-associated fibroblasts (CAFs), suppresses tumorigenesis. Gas1 in these CAFs is activated by the Wnt/β-catenin signaling and the level of CD143+ CAFs predicts better survival in CRC patients [1]. In gastric adenocarcinoma, loss of ATOH1 downregulates Gas1, which then activates the RET/AKT/mTOR signaling pathway, promoting cancer stemness and chemoresistance [5].

In summary, Gas1 plays essential roles in embryonic development, such as in tooth patterning, and in disease conditions like colorectal and gastric cancers. Gene knockout models, especially in mice, have been instrumental in revealing its functions in these biological processes and disease areas, highlighting its potential as a therapeutic target.

References:

1. Chen, Shujie, Fan, Lina, Lin, Yifeng, Si, Jianmin, Wang, Liangjing. 2023. Bifidobacterium adolescentis orchestrates CD143+ cancer-associated fibroblasts to suppress colorectal tumorigenesis by Wnt signaling-regulated GAS1. In Cancer communications (London, England), 43, 1027-1047. doi:10.1002/cac2.12469. https://pubmed.ncbi.nlm.nih.gov/37533188/

2. Schueler-Furman, Ora, Glick, Eitan, Segovia, José, Linial, Michal. 2006. Is GAS1 a co-receptor for the GDNF family of ligands? In Trends in pharmacological sciences, 27, 72-7. doi:. https://pubmed.ncbi.nlm.nih.gov/16406089/

3. Segovia, José, Zarco, Natanael. . Gas1 is a pleiotropic regulator of cellular functions: from embryonic development to molecular actions in cancer gene therapy. In Mini reviews in medicinal chemistry, 14, 1139-47. doi:. https://pubmed.ncbi.nlm.nih.gov/25429664/

4. Seppala, M, Thivichon-Prince, B, Xavier, G M, Viriot, L, Cobourne, M T. 2021. Gas1 Regulates Patterning of the Murine and Human Dentitions through Sonic Hedgehog. In Journal of dental research, 101, 473-482. doi:10.1177/00220345211049403. https://pubmed.ncbi.nlm.nih.gov/34796774/

5. Zhong, Qing, Wang, Hua-Gen, Yang, Ji-Hong, Chen, Qi-Yue, Huang, Chang-Ming. 2023. Loss of ATOH1 in Pit Cell Drives Stemness and Progression of Gastric Adenocarcinoma by Activating AKT/mTOR Signaling through GAS1. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 10, e2301977. doi:10.1002/advs.202301977. https://pubmed.ncbi.nlm.nih.gov/37824217/