Notch4, a member of the Notch receptor family, is involved in crucial biological processes such as cell differentiation, proliferation, and angiogenesis. It is part of the Notch signaling pathway, which plays a central role in development and tissue homeostasis. Genetic models, including knockout (KO) and conditional knockout (CKO) mouse models, have been instrumental in studying Notch4's functions [1,2,3,4,5,6,7,8,9].

In various disease conditions, Notch4 has been shown to have significant impacts. In viral infections like COVID-19, increased Notch4 expression on regulatory T (Treg) cells is associated with disease severity, and deletion of Notch4 in Treg cells normalizes innate immunity [1]. In asthma, interleukin-6-and STAT3-dependent upregulation of Notch4 on lung Treg cells promotes airway inflammation, and Notch4 subverts Treg cells into effector T cells [2]. In atherosclerosis, disturbed blood flow activates the JAG1-NOTCH4 signaling pathway, and EC-specific deletion of Jag1 reduces atherosclerosis [5]. In HIV-1-associated nephropathy, global deletion of the Notch4 intracellular domain improves renal function and decreases inflammation [7]. In FLT3/ITD acute myeloid leukemia, inhibition of NOTCH4 sensitizes cells to FLT3 tyrosine kinase inhibition [8]. In pancreatic tumorigenesis, inactivation of Notch4 in mouse models significantly reduces tumor burden and improves survival [9].

In conclusion, Notch4 plays a vital role in multiple biological processes and is implicated in various diseases, including viral infections, asthma, atherosclerosis, HIV-1-associated nephropathy, leukemia, and pancreatic cancer. The use of KO and CKO mouse models has been crucial in uncovering these disease-related functions, providing potential therapeutic targets for these conditions.