Claus Oxvig

Pregnancy-associated plasma protein-A2 modulates development of cranial cartilage and angiogenesis in zebrafish embryos

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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.

Original languageEnglish
JournalJournal of Cell Science
ISSN0021-9533
DOIs
Publication statusPublished - 18 Sep 2014

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