title: Papp-a2 modulates development of cranial cartilage and angiogenesis in zebrafish embryos.
abstract: Pregnancy-associated plasma protein A2 (PAPP-A2, also known as pappalysin-2) is a large metalloproteinase that is known to be required for normal postnatal growth and bone development in mice. We here report the detection of zebrafish papp-a2 mRNA in the chordamesoderm, notochord and lower jaw of zebrafish (Danio rerio) embryos, and that papp-a2-knockdown embryos display broadened axial mesoderm, notochord bends and severely reduced cranial cartilages. Genetic data link these phenotypes to insulin-like growth factor (Igf)-binding protein-3 (Igfbp-3) and bone morphogenetic protein (Bmp) signaling, and biochemical analysis show specific Igfbp-3 proteolysis by Papp-a2, implicating Papp-a2 in the modulation of Bmp signaling by Igfbp-3 proteolysis. Knockdown of papp-a2 additionally resulted in angiogenesis defects, strikingly similar to previous observations in embryos with mutations in components of the Notch system. Accordingly, we find that Notch signaling is modulated by Papp-a2 in vivo, and, furthermore, that human PAPP-A2 is capable of modulating Notch signaling independently of its proteolytic activity in cell culture. Based on these results, we conclude that Papp-a2 modulates Bmp and Notch signaling by independent mechanisms in zebrafish embryos. In conclusion, these data link pappalysin function in zebrafish to two different signaling pathways outside the IGF system.
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10C, DK-8000 Aarhus C, Denmark.
authors.forename: Kasper
authors.initials: K
authors.lastname: Kjaer-Sorensen
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10C, DK-8000 Aarhus C, Denmark.
authors.forename: Ditte H
authors.initials: DH
authors.lastname: Engholm
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10C, DK-8000 Aarhus C, Denmark.
authors.forename: Malene R
authors.initials: MR
authors.lastname: Jepsen
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10C, DK-8000 Aarhus C, Denmark.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Morch
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10C, DK-8000 Aarhus C, Denmark.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Weyer
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10C, DK-8000 Aarhus C, Denmark.
authors.forename: Louise L
authors.initials: LL
authors.lastname: Hefting
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10C, DK-8000 Aarhus C, Denmark.
authors.forename: Louise L
authors.initials: LL
authors.lastname: Skov
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10C, DK-8000 Aarhus C, Denmark.
authors.forename: Lisbeth S
authors.initials: LS
authors.lastname: Laursen
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10C, DK-8000 Aarhus C, Denmark co@mb.au.dk.
authors.forename: Claus
authors.initials: C
authors.lastname: Oxvig
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism; D002356:Cartilage / Q000196:embryology / Q000201:enzymology*; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D055785:Gene Knockdown Techniques; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000378:metabolism; D008969:Molecular Sequence Data; D018919:Neovascularization, Physiologic; D010641:Phenotype; D011266:Pregnancy-Associated Plasma Protein-A / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D012886:Skull / Q000196:embryology / Q000201:enzymology*; D013997:Time Factors; D014162:Transfection; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D019485:Bone Morphogenetic Proteins; D018972:Insulin-Like Growth Factor Binding Protein 3; D018974:Insulin-Like Growth Factor Binding Protein 4; D012333:RNA, Messenger; D051880:Receptors, Notch; D029961:Zebrafish Proteins; C430889:PAPPA2 protein, human; D011266:Pregnancy-Associated Plasma Protein-A
keywords: Bmp; Igfbp-3; Notch; Papp-a2; Pappa2; Zebrafish