Nr4a1, also known as nuclear receptor 4A1, is a ligand-activated transcription factor that belongs to the NR4A subfamily of nuclear receptors. It plays crucial roles in multiple biological processes, participating in pathways related to cell proliferation, apoptosis, inflammation, and fibrosis [1,3,6]. Genetic models, especially knockout (KO) mouse models, have been instrumental in understanding its functions.

In intestinal fibrosis, Nr4a1-/-mice showed increased colonic thickening and extracellular matrix (ECM) content, indicating that Nr4a1 negatively regulates intestinal fibrosis by dampening fibrogenic signaling in myofibroblasts [1]. Deleting Nr4a1 in CA1 pyramidal neurons of mice led to impaired cognition and excitatory synaptic function, suggesting its role in age-dependent cognitive decline [2]. In the context of cell proliferation and apoptosis, NR4A1 forms a regulatory loop with YAP, where YAP regulates NR4A1, and NR4A1 in turn acts as a feedback inhibitor of YAP [3]. In cancer, NR4A1-deleted breast cancer cells showed massive chromosomal instability and proliferative failure due to deregulated expression of its target gene FOS, highlighting its role in suppressing replication stress [4]. In bone regeneration, Nr4a1-overexpressing bone marrow mesenchymal stem cells (BMSCs) had enhanced osteogenesis, while in renal interstitial fibrosis, Nr4a1 promoted fibrosis through activating p38 MAPK in a mouse model [5,6].

In summary, Nr4a1 is involved in a wide range of biological functions, including cognitive function, cell proliferation, apoptosis, and tissue fibrosis. The use of KO mouse models has significantly contributed to understanding its role in diseases such as intestinal fibrosis, cognitive decline, cancer, bone regeneration disorders, and renal interstitial fibrosis. These findings suggest that Nr4a1 could be a potential therapeutic target for these disease areas.

References:

1. Pulakazhi Venu, Vivek Krishna, Alston, Laurie, Iftinca, Mircea, Altier, Christophe, Hirota, Simon A. 2021. Nr4A1 modulates inflammation-associated intestinal fibrosis and dampens fibrogenic signaling in myofibroblasts. In American journal of physiology. Gastrointestinal and liver physiology, 321, G280-G297. doi:10.1152/ajpgi.00338.2019. https://pubmed.ncbi.nlm.nih.gov/34288735/

2. Chen, Jiang, Zhang, Zhi, Liu, Ying, Zhu, Xiaolei, Xu, Yun. 2024. Progressive reduction of nuclear receptor Nr4a1 mediates age-dependent cognitive decline. In Alzheimer's & dementia : the journal of the Alzheimer's Association, 20, 3504-3524. doi:10.1002/alz.13819. https://pubmed.ncbi.nlm.nih.gov/38605605/

3. He, Lingli, Yuan, Liang, Yu, Wentao, Zhang, Yonglong, Zhang, Lei. . A Regulation Loop between YAP and NR4A1 Balances Cell Proliferation and Apoptosis. In Cell reports, 33, 108284. doi:10.1016/j.celrep.2020.108284. https://pubmed.ncbi.nlm.nih.gov/33086070/

4. Guo, Hongshan, Golczer, Gabriel, Wittner, Ben S, Lawrence, Michael S, Haber, Daniel A. . NR4A1 regulates expression of immediate early genes, suppressing replication stress in cancer. In Molecular cell, 81, 4041-4058.e15. doi:10.1016/j.molcel.2021.09.016. https://pubmed.ncbi.nlm.nih.gov/34624217/

5. Gao, Yangshuai, Zou, Yuming, Sokolowskei, Dimitri, Xu, Jiajia, Zhang, Zhongmin. 2024. Nr4a1 enhances Wnt4 transcription to promote mesenchymal stem cell osteogenesis and alleviates inflammation-inhibited bone regeneration. In Molecular therapy : the journal of the American Society of Gene Therapy, 32, 1479-1496. doi:10.1016/j.ymthe.2024.02.034. https://pubmed.ncbi.nlm.nih.gov/38429926/

6. Tao, Yilin, Tang, Chengyuan, Wei, Ju, Fang, Xi, Li, Ying. 2023. Nr4a1 promotes renal interstitial fibrosis by regulating the p38 MAPK phosphorylation. In Molecular medicine (Cambridge, Mass.), 29, 63. doi:10.1186/s10020-023-00657-y. https://pubmed.ncbi.nlm.nih.gov/37161357/