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Gene Review

Dll4  -  delta-like 4 (Drosophila)

Mus musculus

Synonyms: Delta-like protein 4, Delta4, Drosophila Delta homolog 4
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Disease relevance of Dll4


High impact information on Dll4

  • These results demonstrate that vascular remodeling in the mouse embryo is sensitive to Dll4 gene dosage and that Notch activation in endothelial cells is essential for embryonic vascular remodeling [3].
  • The activity and expression of Dll4 and the known actions of other members of this family suggest a role for Dll4 in the control of endothelial cell biology [4].
  • In situ analysis reveals a highly selective expression pattern of Dll4 within the vascular endothelium [4].
  • These striking phenotypes resulting from heterozygous deletion of Dll4 indicate that vascular development may be as sensitive to subtle changes in Dll4 dosage as it is to subtle changes in VEGF dosage, because VEGF accounts for the only other example of haploid insufficiency, resulting in obvious vascular abnormalities [5].
  • We generated mice in which the Dll4 gene was replaced with a reporter gene, and found that Dll4 expression is initially restricted to large arteries in the embryo, whereas in adult mice and tumor models, Dll4 is specifically expressed in smaller arteries and microvessels, with a striking break in expression just as capillaries merge into venules [5].

Biological context of Dll4


Anatomical context of Dll4

  • Dll4 mRNA is strongly expressed in endothelial cells at the very tips of growing vessels ('tip cells') and also in arteries, where it is expressed in a segmented 'tiger's tail' pattern [8].
  • BM, spleen, lymph nodes, and peripheral blood of Dll4-overexpressing mice contained predominantly CD4(+)CD8(+) T cells and virtually lacked B cells [1].
  • White blood cell and lymphocyte counts in Dll4-overexpressing mice were reduced at the early stage of reconstitution but increased significantly at approximately 10 weeks after BM transplantation [1].
  • The biological role of a novel Notch ligand, Dll4, in mice was explored by reconstituting lethally irradiated mice with bone marrow (BM) cells transduced with Dll4 retroviral vector [1].
  • We investigated the expressions of Delta like (Dll) 1 and Dll4 in the mouse thymus anlages [9].

Regulatory relationships of Dll4

  • These results indicate that expressions of Dll1 and Dll4 in thymic epithelial cells are regulated by Foxn1 transcriptional factor [9].
  • In summary, Dll4 appears to be a major trigger of Notch receptor activities previously implicated in arterial and vascular development, and it may represent a new opportunity for pro- and anti-angiogenic therapies [5].
  • Interference with Dll4-Notch signaling may be particularly desirable in tumors that have highly induced Dll4-Notch pathway [10].

Other interactions of Dll4


Analytical, diagnostic and therapeutic context of Dll4

  • In this study, we report that, in contrast to fetal thymic organ cultures, TSMC fail to maintain expression of the Notch ligands, Delta-like (Dll) 1 and Dll4, and concomitantly lose the ability to support T lymphopoiesis [6].


  1. A novel Notch ligand, Dll4, induces T-cell leukemia/lymphoma when overexpressed in mice by retroviral-mediated gene transfer. Yan, X.Q., Sarmiento, U., Sun, Y., Huang, G., Guo, J., Juan, T., Van, G., Qi, M.Y., Scully, S., Senaldi, G., Fletcher, F.A. Blood (2001) [Pubmed]
  2. Oxygen modifies artery differentiation and network morphogenesis in the retinal vasculature. Claxton, S., Fruttiger, M. Dev. Dyn. (2005) [Pubmed]
  3. Haploinsufficient lethality and formation of arteriovenous malformations in Notch pathway mutants. Krebs, L.T., Shutter, J.R., Tanigaki, K., Honjo, T., Stark, K.L., Gridley, T. Genes Dev. (2004) [Pubmed]
  4. Dll4, a novel Notch ligand expressed in arterial endothelium. Shutter, J.R., Scully, S., Fan, W., Richards, W.G., Kitajewski, J., Deblandre, G.A., Kintner, C.R., Stark, K.L. Genes Dev. (2000) [Pubmed]
  5. Haploinsufficiency of delta-like 4 ligand results in embryonic lethality due to major defects in arterial and vascular development. Gale, N.W., Dominguez, M.G., Noguera, I., Pan, L., Hughes, V., Valenzuela, D.M., Murphy, A.J., Adams, N.C., Lin, H.C., Holash, J., Thurston, G., Yancopoulos, G.D. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  6. Three-dimensional architecture of the thymus is required to maintain delta-like expression necessary for inducing T cell development. Mohtashami, M., Zúñiga-Pflücker, J.C. J. Immunol. (2006) [Pubmed]
  7. Expression of Dll4 during mouse embryogenesis suggests multiple developmental roles. Benedito, R., Duarte, A. Gene Expr. Patterns (2005) [Pubmed]
  8. Periodic Delta-like 4 expression in developing retinal arteries. Claxton, S., Fruttiger, M. Gene Expr. Patterns (2004) [Pubmed]
  9. Lack of Delta like 1 and 4 expressions in nude thymus anlages. Tsukamoto, N., Itoi, M., Nishikawa, M., Amagai, T. Cell. Immunol. (2005) [Pubmed]
  10. Inhibition of Dll4-mediated signaling induces proliferation of immature vessels and results in poor tissue perfusion. Scehnet, J.S., Jiang, W., Kumar, S.R., Krasnoperov, V., Trindade, A., Benedito, R., Djokovic, D., Borges, C., Ley, E.J., Duarte, A., Gill, P.S. Blood (2007) [Pubmed]
  11. Developmental expression of the Notch signaling pathway genes during mouse preimplantation development. Cormier, S., Vandormael-Pournin, S., Babinet, C., Cohen-Tannoudji, M. Gene Expr. Patterns (2004) [Pubmed]
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