Nr6a1, the Nuclear Receptor subfamily 6 group A member 1, is an orphan nuclear receptor with no close evolutionary homologs [2]. It plays a crucial role in regulating key pluripotency and developmental genes. Nr6a1 is also involved in pathways related to embryonic development, such as controlling Hox expression dynamics which is vital for vertebrate trunk development [3].

In mouse models, Nr6a1 was found to be essential for timely Hox signatures progression and cell fate choice within axial progenitors, controlling vertebral number and trunk segmentation [3]. In HepG2 cells, knockdown of Nr6a1 led to increased lipid accumulation, insulin-induced proliferation, and migration, indicating its role in lipid metabolism regulation [5]. In mice, increased hippocampal Nr6a1 impaired the CREB-BDNF signaling cascade, leading to depression-like behaviors [4]. Also, in zebrafish, knockdown of Nr6a1 paralogs resulted in abnormal eye and somite development, suggesting its importance in eye and vertebral development [6,7].

In summary, Nr6a1 is a significant regulator in multiple biological processes including development, lipid metabolism, and neuronal signaling. Model-based research, especially gene knockdown in mice and zebrafish, has revealed its crucial roles in diseases like hepatocellular carcinoma, depression, and the novel oculo-vertebral-renal (OVR) syndrome, providing potential therapeutic targets and insights into disease mechanisms [1,4,6,7].

References:

1. Wu, Qinjuan, Li, Xin, Long, Menghong, Xie, Xianfeng, Liu, Qing. 2023. Integrated analysis of histone lysine lactylation (Kla)-specific genes suggests that NR6A1, OSBP2 and UNC119B are novel therapeutic targets for hepatocellular carcinoma. In Scientific reports, 13, 18642. doi:10.1038/s41598-023-46057-4. https://pubmed.ncbi.nlm.nih.gov/37903971/

2. Li, Jingxuan, Mascarinas, Pauline, McGlinn, Edwina. 2024. The expanding roles of Nr6a1 in development and evolution. In Frontiers in cell and developmental biology, 12, 1357968. doi:10.3389/fcell.2024.1357968. https://pubmed.ncbi.nlm.nih.gov/38440075/

3. Chang, Yi-Cheng, Manent, Jan, Schroeder, Jan, Trainor, Paul, McGlinn, Edwina. 2022. Nr6a1 controls Hox expression dynamics and is a master regulator of vertebrate trunk development. In Nature communications, 13, 7766. doi:10.1038/s41467-022-35303-4. https://pubmed.ncbi.nlm.nih.gov/36522318/

4. Tan, Pingping, Xue, Ting, Wang, Yue, Huang, Chao, Lu, Xu. 2022. Hippocampal NR6A1 impairs CREB-BDNF signaling and leads to the development of depression-like behaviors in mice. In Neuropharmacology, 209, 108990. doi:10.1016/j.neuropharm.2022.108990. https://pubmed.ncbi.nlm.nih.gov/35183538/

5. Wang, Yinfang, Wan, Xiaohong, Hao, Yilong, Wang, Nanping, Zhang, Peng. 2019. NR6A1 regulates lipid metabolism through mammalian target of rapamycin complex 1 in HepG2 cells. In Cell communication and signaling : CCS, 17, 77. doi:10.1186/s12964-019-0389-4. https://pubmed.ncbi.nlm.nih.gov/31315616/

6. Neelathi, Uma M, Ullah, Ehsan, George, Aman, Guan, Bin, Brooks, Brian P. 2024. Variants in NR6A1 cause a novel oculo-vertebral-renal (OVR) syndrome. In Research square, , . doi:10.21203/rs.3.rs-5375105/v1. https://pubmed.ncbi.nlm.nih.gov/39606449/

7. Neelathi, Uma M, Ullah, Ehsan, George, Aman, Guan, Bin, Brooks, Brian P. 2024. Variants in NR6A1 cause a novel oculo-vertebral-renal (OVR) syndrome. In medRxiv : the preprint server for health sciences, , . doi:10.1101/2024.11.09.24316578. https://pubmed.ncbi.nlm.nih.gov/39606382/