Disease relevance of Dll4

• The Dll4-overexpressing mice eventually developed a lethal phenotype that was characterized by the progression of a T-cell lymphoproliferative disease (restricted to BM and lymphoid tissues) to transplantable monoclonal T-cell leukemia/lymphoma scattered to multiple organs [1].
• Forming retinal arteries fail to express the artery-specific markers Delta-like 4 (Dll4) and EphrinB2 during hypoxia [2].

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

• Importantly, ectopic re-expression of Dll1 or Dll4 is sufficient to restore the ability of TSMC to support T lymphopoiesis [6].
• Expression of Dll4 during mouse embryogenesis suggests multiple developmental roles [7].

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

• We studied expression of Notch 1-4 and its ligand Delta-like 4 (Dll4) in the developing retinal vasculature [8].
• However, PDGF-B expression is neither as artery-specific nor as clearly segmented as Dll4 [8].
• In contrast, epithelial cells of the nude thymus anlages express neither Dll1 nor Dll4 [9].
• Notch4 and Dll-4 mRNAs are synthesized from the 2-cell through to the hatched blastocyst stage [11].

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].

References