Control of endothelial sprouting by a Tel-CtBP complex.
We show that the transcriptional repressor Tel plays an evolutionarily conserved role in angiogenesis: it is indispensable for the sprouting of human endothelial cells and for normal development of the Danio rerio blood circulatory system. Tel orchestrates endothelial sprouting by binding to the generic co-repressor, CtBP. The Tel-CtBP complex temporally restricts a VEGF (vascular endothelial growth factor)-mediated pulse of dll4 expression and thereby directly links VEGF receptor intracellular signalling and intercellular Notch-Dll4 signalling. It further controls branching by regulating expression of other factors that constrain angiogenesis such as sprouty family members and ve-cadherin. Thus, the Tel-CtBP complex conditions endothelial cells for angiogenesis by controlling the balance between stimulatory and antagonistic sprouting cues. Tel control of branching seems to be a refinement of invertebrate tracheae morphogenesis that requires Yan, the invertebrate orthologue of Tel. This work highlights Tel and its associated networks as potential targets for the development of therapeutic strategies to inhibit pathological angiogenesis.
Roukens
M Guy
MG
Leiden University Medical Center (LUMC), Section of Growth Control and Transcription, Department of Molecular Cell Biology, 2300 RC Leiden, The Netherlands.
Alloul-Ramdhani
Mariam
M
Baan
Bart
B
Kobayashi
Kazuki
K
Peterson-Maduro
Josi
J
van Dam
Hans
H
Schulte-Merker
Stefan
S
Baker
David A
DA
D000429:Alcohol Oxidoreductases / Q000378:metabolism*; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D016384:Consensus Sequence; D004268:DNA-Binding Proteins / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism*; D005136:Eye Proteins; D006801:Humans; D008969:Molecular Sequence Data; D009243:NAD / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000502:physiology*; D011485:Protein Binding; D050783:Proto-Oncogene Proteins c-ets / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism; D000097764:ETS Translocation Variant 6 Protein
D000429:Alcohol Oxidoreductases; D004268:DNA-Binding Proteins; D005136:Eye Proteins; D009243:NAD; D050783:Proto-Oncogene Proteins c-ets; D012097:Repressor Proteins; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D029961:Zebrafish Proteins; D000097764:ETS Translocation Variant 6 Protein; C553158:ETV6 protein, zebrafish; C577847:ctbp2a protein, zebrafish; C096794:C-terminal binding protein