ABSTRACT
Notch and Angiopoietin-1 (Ang1)/Tie2 pathways are crucial for vascular maturation and stability. Here we identify the transcription factor ERG as a key regulator of endothelial Notch signalling. We show that ERG controls the balance between Notch ligands by driving Delta-like ligand 4 (Dll4) while repressing Jagged1 (Jag1) expression. In vivo, this regulation occurs selectively in the maturing plexus of the mouse developing retina, where Ang1/Tie2 signalling is active. We find that ERG mediates Ang1-dependent regulation of Notch ligands and is required for the stabilizing effects of Ang1 in vivo. We show that Ang1 induces ERG phosphorylation in a phosphoinositide 3-kinase (PI3K)/Akt-dependent manner, resulting in ERG enrichment at Dll4 promoter and multiple enhancers. Finally, we demonstrate that ERG directly interacts with Notch intracellular domain (NICD) and ß-catenin and is required for Ang1-dependent ß-catenin recruitment at the Dll4 locus. We propose that ERG coordinates Ang1, ß-catenin and Notch signalling to promote vascular stability.
Subject(s)
Angiopoietin-1/metabolism , Receptors, Notch/metabolism , Vascular Remodeling , Adaptor Proteins, Signal Transducing , Animals , Calcium-Binding Proteins , Female , Human Umbilical Vein Endothelial Cells , Humans , Intercellular Signaling Peptides and Proteins/metabolism , Jagged-1 Protein/metabolism , Male , Mice, Inbred C57BL , Phosphatidylinositol 3-Kinases/metabolism , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolism , Transcriptional Regulator ERG/metabolism , Wnt Signaling PathwayABSTRACT
In Romania, cystic echinococcosis is endemic and affects, besides humans, various animal species including sheep, cattle, and swine. As yet, no molecular-genetic typing has been carried out to clearly identify the putative strains being transmitted there. Parasite samples (protoscoleces or germinal layers) were collected from infected intermediate hosts and subsequently analyzed by comparing the PCR-amplified DNA sequences of three targets: one nuclear (BG1/3) and two mitochondrial (cox1 and nadI). Three strains were identified with the mitochondrial sequences: (i) the common sheep strain (G1) which circulates between sheep and cattle and is infective for humans, (ii) the Tasmanian sheep strain (G2) infecting sheep and cattle, and (iii) the pig strain (G7) predominantly found in swine. To our knowledge, this is the first report which demonstrates the occurrence of the Tasmanian sheep strain in cattle and the sympatric occurrence of these three strains (G1, G2, and G7) in Europe.
Subject(s)
Echinococcosis, Hepatic/parasitology , Echinococcosis, Pulmonary/parasitology , Echinococcus granulosus/classification , Echinococcus granulosus/genetics , Animals , Base Sequence , Cattle , Cattle Diseases/parasitology , DNA, Helminth/analysis , DNA, Helminth/isolation & purification , DNA, Mitochondrial/analysis , DNA, Protozoan/analysis , Echinococcus granulosus/isolation & purification , Genotype , Helminth Proteins/chemistry , Helminth Proteins/genetics , Humans , Molecular Sequence Data , NADH Dehydrogenase , Polymerase Chain Reaction , Romania , Sheep , Sheep Diseases/parasitology , Swine Diseases/parasitologyABSTRACT
Geminin is a multifunctional protein. After DNA replication is initiated during a cell cycle, geminin binds to Cdt1, one of the key DNA replication licensing factors. This highly regulated interaction sequestrates Cdt1, thus preventing DNA rereplication in the same cell cycle. In addition, geminin directly interacts with Six3 and Hox homeodomain proteins during embryogenesis and inhibits their functions. The regulation of Hox function by geminin also involves a transient association with the Hox repressive Polycomb complex. The functions of geminin to obstruct key molecules of both cell proliferation and embryonic development suggest a competitive coordination of these two processes.
