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HGNC Approved Gene Symbol: NOTCH4
Cytogenetic location: 6p21.32 Genomic coordinates (GRCh38): 6:32,194,843-32,224,067 (from NCBI)
Notch proteins are single-pass transmembrane receptors that regulate cell fate decisions during development. The Notch family includes 4 receptors, NOTCH1 (190198), NOTCH2 (600275), NOTCH3 (600276), and NOTCH4, whose ligands include JAG1 (601920), JAG2 (602570), DLL1 (606582), DLL3 (602768), and DLL4 (605185). All of the receptors have an extracellular domain containing multiple epidermal growth factor (EGF; 131530)-like repeats and an intracellular region containing the RAM domain, ankyrin repeats, and a C-terminal PEST domain (Das et al., 2004).
Uyttendaele et al. (1996) cloned cDNAs corresponding to the complete coding region of the mouse Int3 gene. They proposed renaming this gene Notch4, and reserving Int3 for the truncated oncogene that contains only the transmembrane and intracellular domains of Notch4. In situ hybridization revealed that Notch4 transcripts are primarily restricted to endothelial cells in embryonic and adult life, suggesting a specific role for Notch4 during development of vertebrate endothelium.
Li et al. (1998) isolated cDNAs corresponding to 6.7-kb NOTCH4(S) and 9.3-kb NOTCH4(L) mRNA isoforms. The predicted protein encoded by NOTCH4(S) is 2,003 amino acids long and contains the characteristic Notch motifs: a signal peptide, 29 epidermal growth factor (EGF)-like repeats, 3 Notch/lin-12 repeats, a transmembrane region, 6 cdc10 (603151)/ankyrin (see 600465) repeats, and the PEST conserved region at the C terminus. The sequences of the mouse and human NOTCH4 proteins are 82% identical. The incompletely spliced NOTCH4(L) cDNA potentially encodes 2 different proteins. One consists of the first 7 EGF repeats. The second contains the transmembrane domain and intracellular region and is similar to the mouse int3 protooncoprotein. Northern blot analysis revealed that NOTCH4(S) is the major transcript and is expressed in a wide variety of tissues.
Li et al. (1998) reported that the NOTCH4 gene contains 30 exons and spans approximately 30 kb.
Sugaya et al. (1994) identified the NOTCH4 gene while conducting a chromosome walk in the class III region of the major histocompatibility complex (MHC) near the junction with class II. Fluorescence in situ hybridization confirmed the location of the NOTCH4 gene at chromosome 6p21.3.
Sugaya et al. (1997) noted that 10 genes mapped on 6p21.3, including NOTCH4, had counterparts structurally and functionally similar to those mapped on 9q33-q34, indicating segmental chromosome duplication during the course of evolution.
For discussion of a possible association between variation in the NOTCH4 gene and risk of schizophrenia, see SCZD3 (600511).
The Notch gene family encodes large transmembrane receptors that are components of an evolutionarily conserved intercellular signaling mechanism. To assess the role of the NOTCH4 gene, Krebs et al. (2000) generated Notch4-deficient mice by gene targeting. Embryos homozygous for this mutation developed normally, and homozygous mutant adults were viable and fertile. However, the Notch4 mutation displayed genetic interactions with a targeted mutation of the related Notch1 gene. Embryos homozygous for mutations of both the Notch4 and Notch1 genes often displayed a more severe phenotype than Notch1 homozygous mutant embryos. Both Notch1 mutant and Notch1/Notch4 double mutant embryos displayed severe defects in angiogenic vascular remodeling. Analysis of the expression patterns of genes encoding ligands for Notch family receptors indicated that only the Dll4 (DLL4; 605185) gene is expressed in a pattern consistent with that expected for a gene encoding a ligand for the Notch1 and Notch4 receptors in the early embryonic vasculature. Krebs et al. (2000) stated that these results reveal an essential role for the Notch signaling pathway in regulating embryonic vascular morphogenesis and remodeling, and indicate that whereas the Notch4 gene is not essential during embryonic development, the Notch4 and Notch1 genes have partially overlapping roles during embryogenesis in mice.
Murphy et al. (2008) generated mice with constitutively active Notch4 expression in endothelial cells from birth by using a tetracycline-regulatable system. By 3 weeks of age, all mutants developed hallmarks of brain arteriovenous malformations (BAVM; 108010), including cerebral arteriovenous shunting and vessel enlargement, followed by death by 5 weeks of age. Approximately 25% of the mutant mice showed signs of neurologic dysfunction, including ataxia and seizures. Imaging studies detected cerebral arteriovenous malformations. Repression of Notch4 resolved ataxia and reversed the disease progression, demonstrating that Notch4 is not only sufficient to induce but also required to sustain the disease. Postmortem examination showed hemorrhage and neuronal cell death within the cerebral cortex and cerebellum, as well as widespread enlargement of the cerebral microvasculature, which coincided with a reduction in capillary density. These findings suggested that vessel enlargement underlies the development of BAVM and linked this pathology to the known function of NOTCH pathway as an inhibitor of vessel sprouting.
Das, I., Craig, C., Funahashi, Y., Jung, K.-M., Kim, T.-W., Byers, R., Weng, A. P., Kutok, J. L., Aster, J. C., Kitajewski, J. Notch oncoproteins depend on gamma-secretase/presenilin activity for processing and function. J. Biol. Chem. 279: 30771-30780, 2004. [PubMed: 15123653] [Full Text: https://doi.org/10.1074/jbc.M309252200]
Krebs, L. T., Xue, Y., Norton, C. R., Shutter, J. R., Maguire, M., Sundberg, J. P., Gallahan, D., Closson, V., Kitajewski, J., Callahan, R., Smith, G. H., Stark, K. L., Gridley, T. Notch signaling is essential for vascular morphogenesis in mice. Genes Dev. 14: 1343-1352, 2000. [PubMed: 10837027]
Li, L., Huang, G. M., Banta, A. B., Deng, Y., Smith, T., Dong, P., Friedman, C., Chen, L., Trask, B. J., Spies, T., Rowen, L., Hood, L. Cloning, characterization, and the complete 56.8-kilobase DNA sequence of the human NOTCH4 gene. Genomics 51: 45-58, 1998. [PubMed: 9693032] [Full Text: https://doi.org/10.1006/geno.1998.5330]
Murphy, P. A., Lam, M. T. Y., Wu, X., Kim, T. N., Vartanian, S. M., Bollen, A. W., Carlson, T. R., Wang, R. A. Endothelial Notch4 signaling induces hallmarks of brain arteriovenous malformations in mice. Proc. Nat. Acad. Sci. 105: 10901-10906, 2008. [PubMed: 18667694] [Full Text: https://doi.org/10.1073/pnas.0802743105]
Sugaya, K., Fukagawa, T., Matsumoto, K., Mita, K., Takahashi, E., Ando, A., Inoko, H., Ikemura, T. Three genes in the human MHC class III region near the junction with the class II: gene for receptor of advanced glycosylation end products, PBX2 homeobox gene and a Notch homolog, human counterpart of mouse mammary tumor gene int-3. Genomics 23: 408-419, 1994. [PubMed: 7835890] [Full Text: https://doi.org/10.1006/geno.1994.1517]
Sugaya, K., Sasanuma, S., Nohata, J., Kimura, T., Fukagawa, T., Nakamura, Y., Ando, A., Inoko, H., Ikemura, T., Mita, K. Gene organization of human NOTCH4 and (CTG)n polymorphism in this human counterpart gene of mouse proto-oncogene Int3. Gene 189: 235-244, 1997. [PubMed: 9168133] [Full Text: https://doi.org/10.1016/s0378-1119(96)00857-8]
Uyttendaele, H., Marazzi, G., Wu, G., Yan, Q., Sassoon, D., Kitajewski, J. Notch4/int-3, a mammary proto-oncogene, is an endothelial cell-specific mammalian Notch gene. Development 122: 2251-2259, 1996. [PubMed: 8681805] [Full Text: https://doi.org/10.1242/dev.122.7.2251]