NOTCH4 INT-3, A MAMMARY PROTOONCOGENE, IS AN ENDOTHELIAL CELL-SPECIFIC MAMMALIAN NOTCH GENE/

The int-3 oncogene was identified as a frequent target in Mouse Mammar y Tumor Virus (MMTV)-induced mammary carcinomas and encodes the intrac ellular domain of a novel mouse Notch ge:ne. To investigate the role o f the int-3 proto-oncogene in mouse development and carcinogenesis, we isolated cDNA clones corresponding to the entire coding potential of the int-3 proto-oncogene. We propose to name this gene Notch4 and rese rve the int-3 nomenclature for references to the oncogenic form. The d educed amino acid sequence of Notch4 contains conserved motifs found i n Notch proteins; however Notch4 has fewer epidermal growth factor (EG F)-like repeats and a shorter intracellular domain than other mouse No tch homologues. Comparison of the coding potential of the int-3 gene t o that of Notch4 suggests that loss of the extracellular domain of Not ch4 leads to constitutive activation of this murine Notch protein. In situ hybridization revealed that Notch4 transcripts are primarily rest ricted to endothelial cells in embryonic and adult life. Truncated Not ch4 transcripts were detected in post-meiotic male germ cells. The dis tinct Notch4 protein features and its restricted expression pattern su ggests a specific role for Notch4 during development of vertebrate end othelium.