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Extracellular bone morphogenetic protein modulator BMPER and twisted gastrulation homolog 1 preserve arterial‐venous specification in zebrafish blood vessel development and regulate Notch signaling in endothelial cells
Author(s) -
Esser Jennifer Susanne,
Steiner Rahel Elisabeth,
Deckler Meike,
Schmitt Hannah,
Engert Bianca,
Link Sandra,
Charlet Anne,
Patterson Cam,
Bode Christoph,
Zhou Qian,
Moser Martin
Publication year - 2018
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.14414
Subject(s) - notch signaling pathway , bone morphogenetic protein , zebrafish , microbiology and biotechnology , biology , hes3 signaling axis , signal transduction , morpholino , bone morphogenetic protein 2 , gastrulation , embryo , embryogenesis , genetics , gene , in vitro
The bone morphogenetic protein ( BMP ) signaling pathway plays a central role during vasculature development. Mutations or dysregulation of the BMP pathway members have been linked to arteriovenous malformations. In the present study, we investigated the effect of the BMP modulators bone morphogenetic protein endothelial precursor‐derived regulator ( BMPER ) and twisted gastrulation protein homolog 1 ( TWSG 1) on arteriovenous specification during zebrafish development and analyzed downstream Notch signaling pathway in human endothelial cells. Silencing of bmper and twsg1b in zebrafish embryos by morpholinos resulted in a pronounced enhancement of venous ephrinB4a marker expression and concomitant dysregulated arterial ephrinb2a marker expression detected by in situ hybridization. As arteriovenous specification was disturbed, we assessed the impact of BMPER and TWSG 1 protein stimulation on the Notch signaling pathway on endothelial cells from different origin. Quantitative real‐time PCR (qRT‐PCR) and western blot analysis showed increased expression of Notch target gene hairy and enhancer of split, HEY 1/2 and EPHRINB 2. Consistently, silencing of BMPER in endothelial cells by si RNA s decreased Notch signaling and downstream effectors. BMP receptor antagonist DMH 1 abolished BMPER and BMP 4 induced Notch signaling pathway activation. In conclusion, we found that in endothelial cells, BMPER and TWSG 1 are necessary for regular Notch signaling activity and in zebrafish embryos BMPER and TWSG 1 preserve arteriovenous specification to prevent malformations.