Npas2-flox Mouse

Npas2, encoding the neuronal PAS domain protein 2, is a core component of the molecular clockwork. It binds with DNA at E-box sequences, forms heterodimers with BMAL1, and acts as a pyridine nucleotide-dependent and gas-responsive CO-dependent transcription factor. Npas2 plays regulatory roles in metabolic pathways, is crucial for central nervous system function in mammals, and is involved in normal biological functions like cardiovascular function and wound healing, as well as in carcinogenesis [1,3].

In gene-knockout studies, Npas2-null mice showed decreased CYP1A2 expression and activity in the liver, indicating Npas2 is a key transcriptional regulator of diurnal CYP1A2 expression [7]. In lung adenocarcinoma cells, depletion of Npas2 increased susceptibility to cisplatin treatment, and mRNA sequencing analysis revealed down-regulation of DNA repair-related genes, suggesting Npas2 dampens chemo-sensitivity by enhancing DNA damage repair [2]. In prostate cancer, knockdown of Npas2 inhibited cell proliferation, promoted apoptosis, and suppressed tumor growth in nude mice, along with reduced aerobic glycolysis [4]. In rats, over-expressing Npas2 adenovirus ameliorated myocardial ischemia/reperfusion injury, while knockdown of Cry2 (which interacts with Npas2) aggravated cardiomyocyte apoptosis [5]. Therapeutic down-regulation of Npas2 in a murine model promoted surgical skin wound healing, with faster-healing wounds and less granulation tissue [6]. In mice, Npas2 null mutant mice showed less anxiety-like behavior, and knockdown of Npas2 in the ventral striatum had a similar effect, also reducing Gabra1 expression and response to diazepam [8].

In conclusion, Npas2 is essential for multiple biological functions including circadian regulation, metabolism, and DNA repair. Gene-knockout models have been instrumental in revealing its role in diseases such as cancer, cardiovascular diseases, and psychiatric disorders, providing insights into potential therapeutic targets for these conditions.