title: BMPER, a novel endothelial cell precursor-derived protein, antagonizes bone morphogenetic protein signaling and endothelial cell differentiation.
abstract: The development of endothelial cell precursors is essential for vasculogenesis. We screened for differentially expressed transcripts in endothelial cell precursors in developing mouse embryoid bodies. We cloned a complete cDNA encoding a protein that contains an amino-terminal signal peptide, five cysteine-rich domains, a von Willebrand D domain, and a trypsin inhibitor domain. We termed this protein BMPER (bone morphogenetic protein [BMP]-binding endothelial cell precursor-derived regulator). BMPER is specifically expressed in flk-1-positive cells and parallels the time course of flk-1 induction in these cells. In situ hybridization in mouse embryos demonstrates dorsal midline staining and staining of the aorto-gonadal-mesonephric region, which is known to host vascular precursor cells. BMPER is a secreted protein that directly interacts with BMP2, BMP4, and BMP6 and antagonizes BMP4-dependent Smad5 activation. In Xenopus embryos, ventral injection of BMPER mRNA results in axis duplication and downregulation of the expression of Xvent-1 (downstream target of Smad signaling). In an embryoid body differentiation assay, BMP4-dependent differentiation of endothelial cells in embryoid bodies is also antagonized by BMPER. Taken together, our data indicate that BMPER is a novel BMP-binding protein that is expressed by endothelial cell precursors, has BMP-antagonizing activity, and may play a role in endothelial cell differentiation by modulating local BMP activity.
authors.affiliation: Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Moser
authors.forename: Olav
authors.initials: O
authors.lastname: Binder
authors.forename: Yaxu
authors.initials: Y
authors.lastname: Wu
authors.forename: Julius
authors.initials: J
authors.lastname: Aitsebaomo
authors.forename: Rongqin
authors.initials: R
authors.lastname: Ren
authors.forename: Christoph
authors.initials: C
authors.lastname: Bode
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Bautch
authors.forename: Frank L
authors.initials: FL
authors.lastname: Conlon
authors.forename: Cam
authors.initials: C
authors.lastname: Patterson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D015153:Blotting, Western; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors*; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics* / Q000494:pharmacology*; D002454:Cell Differentiation; D002460:Cell Line; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D005434:Flow Cytometry; D015723:Gene Library; D017930:Genes, Reporter; D006801:Humans; D017403:In Situ Hybridization; D051379:Mice; D008957:Models, Genetic; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051902:Smad5 Protein; D013997:Time Factors; D014018:Tissue Distribution; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D029867:Xenopus Proteins; D014982:Xenopus laevis
chemical_list: C525718:BMP2 protein, human; C525809:BMP4 protein, human; C525816:BMP6 protein, human; C476724:BMPER protein, human; C525719:Bmp2 protein, mouse; C525810:Bmp4 protein, mouse; C525817:Bmp6 protein, mouse; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; C497797:SMAD5 protein, human; D051902:Smad5 Protein; C497800:Smad5 protein, Xenopus; C497798:Smad5 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D029867:Xenopus Proteins; C525812:bmp4 protein, Xenopus; C499469:recombinant human bone morphogenetic protein-2; D012313:RNA; D040301:Vascular Endothelial Growth Factor Receptor-2