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The mouse embryos heterozygous for a targeted mutation in the gene encoding the DLL4 ligand exhibit happloinsufficient lethality because of defects in vascular remodeling is reported. Notch pathway mutant embryos exhibit defects in arterial specification of nascent blood vessels and develop arteriovenous malformations.

Research has been conducted on the role of the Notch4 gene in the intercellular signaling mechanism. The generation of the Notch4-deficient mice by gene targeting is described.

Autoradiographic studies have localized the novel angiotensin IV receptor to the proximal convoluted tubule of the rat kidney. The receptor is found at the apical and the lateral membranes of the proximal tubule cells. Angiotensin IV decreases the transcellular sodium flux in a concentration-dependent manner. Receptor blocking assays and ouabain pretreatment reveal that the angiotensin IV modulates sodium transport by inhibiting the ouabain-sensitive sodium-potassium pump.

Notch3 is required to generate functional arteries in mice by regulating arterial differentiation and maturation of vascular smooth muscle cells (vSMC) and that Notch3 is required for arterial specification of vSMC but not of endothelial cells. The data from observation on Notch3 mice reveal Notch3 to be first cell-autonomous regulator of arterial differentiation and maturation of vSMC.

Research has been conducted on left-right asymmetry generation in the vertebrate body. The authors demonstrate that Notch signaling is important for the asymmetry establishment in mice carrying it out via Nodal gene expression regulation.

We have identified a gene encoding a novel protein that is transcriptionally regulated by the Notch signaling pathway in mammals. This gene, named Nrarp (for Notch-regulated ankyrin-repeat protein), encodes a 114 amino acid protein that has a unique amino-terminus and a carboxy-terminal domain containing two ankyrin-repeat motifs. A Xenopus homolog of the Nrarp gene was previously identified in a large-scale in situ hybridization screen of randomly isolated cDNA clones. We demonstrate that in T-cell and myoblast cell lines expression of the Nrarp gene is induced by the intracellular domain of the Notch1 protein, and that this induction is mediated by a CBF1/Su(H)/Lag. 1 (CSL)-dependent pathway. During mouse embryogenesis, the Nrarp gene is expressed in several tissues in which cellular differentiation is regulated by the Notch signaling pathway. Expression of the Nrarp gene is downregulated in Notch1 null mutant mouse embryos, indicating that expression of the Nrarp gene is regulated by the Notch pathway in vivo. Thus, Nrarp transcript levels are regulated by the level of Notch1 signaling in both cultured cell lines and mouse embryos. During somitogenesis, the Nrarp gene is expressed in a pattern that suggests that Nrarp expression may play a role in the formation of somites, and Nrarp expression in the paraxial mesoderm is altered in several Notch pathway mutants that exhibit defects in somite formation. These observations demonstrate that the Nrarp gene is an evolutionarily conserved transcriptional target of the Notch signaling pathway. Key Words: Notch signaling pathway; downstream target gene; ankyrin repeat.