Dll4, short for Delta-like 4, is a ligand of the Notch signaling pathway. The Notch pathway is highly conserved and controls diverse cellular processes such as growth, differentiation, and patterning. Dll4-Notch signaling is crucial in multiple biological processes including angiogenesis, cell-cell communication, and immune regulation. Genetic models, like gene knockout (KO) or conditional knockout (CKO) mouse models, have been instrumental in understanding its functions [3,4,5,6,7,8,9,10].

In muscle atrophy, inhibition of the Dll4-Notch2 axis in mice prevents disuse-or diabetes-induced muscle atrophy and promotes mechanical overloading-induced muscle hypertrophy, revealing its role in regulating skeletal muscle mass [2]. In diabetic nephropathy, Epsin1-mediated exosomal sorting of Dll4 modulates the tubular-macrophage crosstalk, with Epsin1 knockdown in high-glucose-treated tubular cells reducing macrophage activation and tubulointerstitial damage in mice [1]. In atherosclerotic arteries, genetic deletion of Dll4 from murine endothelial cells reduced markers of endothelial-to-mesenchymal transition (EndMT) and inflammation at a low oscillatory shear stress (LOSS) region of the aorta, indicating its role in ENDMT and inflammation regulation [7].

In conclusion, Dll4, through its interaction with the Notch signaling pathway, plays essential roles in various biological processes and disease conditions. Studies using KO/CKO mouse models have provided insights into its functions in muscle mass regulation, diabetic nephropathy, and atherosclerosis. Understanding Dll4's functions may offer potential therapeutic targets for these and other related diseases.