Nr4a3-flox Mouse

Nr4a3, also known as Neuron-derived Orphan Receptor 1 (NOR-1), is an orphan nuclear receptor belonging to the nuclear receptor subfamily 4 group A. It has no identified natural ligands but can be activated by specific small molecules and receptors. Nr4a3 functions as an early stress factor, regulating processes such as cell differentiation, apoptosis, metabolism, and homeostasis in various tissues and cells [3].

In vascular biology, Nr4a3 -/- mice studies revealed that Nr4a3 promotes vascular calcification. Its deficiency preserved the contractile phenotype of vascular smooth muscle cells, inhibited osteoblast-related gene expression, and reduced calcium deposition. Nr4a3 enhanced glycolysis by binding to the promoter regions of ALDOA and PFKL, increasing lactate production and histone lactylation, which promoted medial calcification. Also, Nr4a3 deficiency inhibited the transcription of Phospho1, and pharmacological inhibition of Phospho1 attenuated calcium deposition in Nr4a3-overexpressed cells [1].

In diabetes-induced atrial cardiomyopathy, Nr4a3 -/- mice showed exacerbated atrial hypertrophy, fibrosis, and increased susceptibility to atrial fibrillation. Overexpression of Nr4a3 in db/db mice alleviated these effects by improving mitochondrial energy metabolism and reducing oxidative stress through preserving Sdha transcriptional expression [2].

In thymic negative selection, Nr4a3 -/- mice had an accumulation of self-reactive thymocytes, suggesting Nr4a3 is necessary to limit their accumulation [4].

In conclusion, Nr4a3 plays crucial roles in multiple biological processes. Model-based research, especially using Nr4a3 knockout mouse models, has revealed its significance in diseases like vascular calcification, diabetes-induced atrial cardiomyopathy, and thymic negative selection. Understanding Nr4a3 function provides insights into disease mechanisms and potential therapeutic targets.