Bmal1-flox Mouse

Bmal1, also known as Brain and muscle arnt-like protein 1, is a crucial transcription factor in the circadian clock. It forms a heterodimer with Clock, binding to the E-box element in the promoters of genes like Per and Cry, regulating the rhythmic expression of circadian-controlled genes. It is associated with multiple biological processes, including immune regulation, metabolism, and reproduction, and thus is of great biological importance. Genetic models, such as knockout (KO) and conditional knockout (CKO) mouse models, are valuable for studying its functions [5].

In the context of disease, Bmal1 down-regulation in cardiomyocyte-specific knockout (CKB) and type 2 diabetes (T2D) mice heart accelerates cardiac hypertrophy and diastolic dysfunction in diabetic cardiomyopathy, while over-expression ameliorates these pathological changes. This occurs through Bcl2/IP3R-mediated mitochondrial Ca2 + overload [1]. Disruption of BMAL1 in mice elicits an endocrine adaption impacting insulin sensitivity and liver disease, showing a different association with fibrosis development compared to humans [2]. In sepsis-induced acute lung injury, BMAL1 deficiency in macrophages exacerbates systemic inflammation and lung injury by up-regulating CXCL2 and intensifying neutrophil-related lung injury [3]. In sepsis-induced acute kidney injury, BMAL1 over-expression alleviates renal tubular injury by reducing ferroptosis levels through inhibiting YAP expression and the Hippo pathway [4]. Bmal1 -/- mutant mice with a non-functional circadian clock show more severe and constant colitis, with disrupted daily rhythms in inflammation and epithelial proliferation [6]. In acute myeloid leukemia, knocking down BMAL1 inhibits cell growth, promotes ferroptosis, and enhances the efficacy of certain cancer drugs [7]. In glioblastoma, silencing BMAL1 promotes M1/M2 polarization through the LDHA/lactate axis, sensitizing cells to bevacizumab [8]. Also, BMAL1-KO mice are infertile, with impaired reproductive organs, gametes, and disrupted hypothalamus-pituitary-gonadal (H-P-G) axis function [9].

In conclusion, Bmal1 plays essential roles in maintaining normal physiological functions, including circadian rhythm regulation, immune homeostasis, metabolism, and reproduction. Studies using Bmal1 KO/CKO mouse models have revealed its significant contributions to various disease areas such as diabetes-related cardiomyopathy, liver diseases, sepsis-related organ injuries, colitis, leukemia, glioblastoma, and reproductive disorders. Understanding Bmal1 function provides insights into disease mechanisms and potential therapeutic targets.