Notch4 Knockout mouse models

Encoding the most divergent family member, Notch4 is the mouse ortholog of human NOTCH4 and produces a receptor with markedly fewer EGF repeats, endothelium-restricted expression, and weaker transactivation than Notch1, still relying on Adam and gamma-secretase processing to liberate an intracellular domain that engages Rbpj and Maml. The locus is historically important as int3, where MMTV proviral insertion truncates the extracellular region and yields a constitutively active intracellular fragment that drives mammary tumors, which established that ligand-independent Notch signaling is transforming. Homozygous nulls are viable and fertile with normal vasculature, and combining them with Notch1 deficiency does not markedly worsen the Notch1 phenotype, so loss-of-function alleles at this locus are of limited value on their own. The productive designs are therefore gain-of-function: endothelial-restricted intracellular domain expression to test arteriovenous malformation and tumor angiogenesis phenotypes, paired with a validated Cdh5-CreER driver so activation timing is controlled rather than constitutive.

Notch4 null animals are straightforward to genotype and phenotype when survival is acceptable. They remain a standard background for pharmacology, biomarker, and rescue studies.