ZFIN ID: ZDB-PUB-140923-23
Papp-a2 modulates development of cranial cartilage and angiogenesis in zebrafish embryos
Kjaer-Sorensen, K., Engholm, D.H., Jepsen, M.R., Morch, M.G., Weyer, K., Hefting, L.L., Skov, L.L., Laursen, L.S., Oxvig, C.
Date: 2014
Source: Journal of Cell Science   127(23): 5027-37 (Journal)
Registered Authors:
Keywords: none
MeSH Terms:
  • Amino Acid Sequence
  • Animals
  • Bone Morphogenetic Proteins/genetics
  • Bone Morphogenetic Proteins/metabolism
  • Cartilage/embryology
  • Cartilage/enzymology*
  • Gene Expression Regulation, Developmental
  • Gene Expression Regulation, Enzymologic
  • Gene Knockdown Techniques
  • Genotype
  • HEK293 Cells
  • Humans
  • Insulin-Like Growth Factor Binding Protein 3/metabolism
  • Insulin-Like Growth Factor Binding Protein 4/metabolism
  • Molecular Sequence Data
  • Neovascularization, Physiologic*
  • Phenotype
  • Pregnancy-Associated Plasma Protein-A/genetics
  • Pregnancy-Associated Plasma Protein-A/metabolism*
  • RNA, Messenger/metabolism
  • Receptors, Notch/genetics
  • Receptors, Notch/metabolism
  • Signal Transduction
  • Skull/embryology
  • Skull/enzymology*
  • Time Factors
  • Transfection
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Zebrafish/metabolism*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed: 25236600 Full text @ J. Cell Sci.
Pregnancy-associated plasma protein-A2 (PAPP-A2, pappalysin-2) is a large metalloproteinase, known to be required for normal postnatal growth and bone development in mice. We here report the detection of zebrafish papp-a2 mRNA in 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 binding protein-3 (Igfbp-3) and 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. Concordantly, we find that Notch signaling is modulated by Papp-a2 in vivo, and, furthermore, that 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.