Nr4a2, also known as Nurr1, is a nuclear receptor and transcription factor. It is widely expressed in the cell nuclei of the central nervous system and is a crucial regulator of dopaminergic (DA) neuronal differentiation, survival, and maintenance. It regulates genes important for dopaminergic signals. Additionally, it has been associated with various physiological processes like inflammation and neuroprotection in the hippocampus, and is involved in metabolic reprogramming in esophageal squamous cell carcinoma [2,3,5]. Genetic models, such as KO/CKO mouse models, are valuable for studying its functions.

In mouse models, overexpression of Nr4a2 in the anterior cingulate cortex reversed LPS-induced depressive-and anxiety-like behaviors, suggesting its role in regulating depressive-like behaviors via microglia and CamkII neurons [1]. In the liver of steatotic mice, Nr4a2 overexpression promoted steatosis-to-NASH progression, while liver-specific Nr4a2 knockout mice were protected from diet-induced NASH, indicating its role in NASH development [4]. Prolonged cardiac Nr4a2 activation in mice led to cardiomyocyte hypertrophy, left ventricular dilation, heart failure, and death, suggesting its role in cardiac self-renewal and heart regeneration [6].

In conclusion, Nr4a2 plays essential roles in neuronal function, mental health, metabolic diseases, and cardiac function. Studies using KO/CKO mouse models have revealed its contributions to diseases such as depression, NASH, and dilated cardiomyopathy, providing insights into potential therapeutic targets for these conditions.

References:

1. He, Yong, Wang, Yue, Yu, Heming, Guo, Yi, Xie, Peng. 2023. Protective effect of Nr4a2 (Nurr1) against LPS-induced depressive-like behaviors via regulating activity of microglia and CamkII neurons in anterior cingulate cortex. In Pharmacological research, 191, 106717. doi:10.1016/j.phrs.2023.106717. https://pubmed.ncbi.nlm.nih.gov/36948326/

2. Català-Solsona, Judit, Miñano-Molina, Alfredo J, Rodríguez-Álvarez, José. 2021. Nr4a2 Transcription Factor in Hippocampal Synaptic Plasticity, Memory and Cognitive Dysfunction: A Perspective Review. In Frontiers in molecular neuroscience, 14, 786226. doi:10.3389/fnmol.2021.786226. https://pubmed.ncbi.nlm.nih.gov/34880728/

3. Jin, Xing, Liu, Lei, Liu, Dan, Liu, Ji-Bin, Chen, Wen-Lian. 2024. Unveiling the methionine cycle: a key metabolic signature and NR4A2 as a methionine-responsive oncogene in esophageal squamous cell carcinoma. In Cell death and differentiation, 31, 558-573. doi:10.1038/s41418-024-01285-7. https://pubmed.ncbi.nlm.nih.gov/38570607/

4. Li, Bo, Yang, Ziyi, Mao, Fei, Jin, Jie, Lu, Yan. 2023. Downregulation of microRNA-145a-5p promotes steatosis-to-NASH progression through upregulation of Nr4a2. In Journal of hepatology, 79, 1096-1109. doi:10.1016/j.jhep.2023.06.019. https://pubmed.ncbi.nlm.nih.gov/37463623/

5. Jakaria, Md, Haque, Md Ezazul, Cho, Duk-Yeon, Kim, In-Su, Choi, Dong-Kug. 2019. Molecular Insights into NR4A2(Nurr1): an Emerging Target for Neuroprotective Therapy Against Neuroinflammation and Neuronal Cell Death. In Molecular neurobiology, 56, 5799-5814. doi:10.1007/s12035-019-1487-4. https://pubmed.ncbi.nlm.nih.gov/30684217/

6. Ashraf, Sadia, Taegtmeyer, Heinrich, Harmancey, Romain. 2022. Prolonged cardiac NR4A2 activation causes dilated cardiomyopathy in mice. In Basic research in cardiology, 117, 33. doi:10.1007/s00395-022-00942-7. https://pubmed.ncbi.nlm.nih.gov/35776225/