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Pregnancy-associated plasma protein-A (PAPP-A) modulates early developmental rate in zebrafish independent of its proteolytic activity

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  • Kasper Kjær-Sørensen
  • Ditte Høyer Engholm
  • Hiroyasu Kamei, University of Michigan, United States
  • Maria Grymer Metz Mørch, Denmark
  • Anisette O Kristensen, Denmark
  • Jianfeng Zhou, University of Michigan, United States
  • Cheryl A. Conover, Mayo Clinic, United States
  • Cunming Duan, University of Michigan, United States
  • Claus Oxvig
Pregnancy-associated plasma protein-A (PAPP-A) is a large metalloproteinase specifically cleaving IGF binding proteins, causing increased IGF bioavailability and hence local regulation of IGF receptor activation. We have identified two highly conserved zebrafish homologs of the human PAPP-A gene. Expression of zebrafish Papp-a, one of the two paralogs, begins during gastrulation and persists throughout the first week of development, and analyses demonstrate highly conserved patterns of expression between adult zebrafish, humans, and mice. We show that the specific knockdown of zebrafish papp-a limits the developmental rate beginning during gastrulation without affecting the normal patterning of the embryo. This phenotype is different from those resulting from deficiency of Igf receptor or ligand in zebrafish, suggesting a function of Papp-a outside the Igf system. Biochemical analysis of recombinant zebrafish Papp-a demonstrates conservation of proteolytic activity, specificity, and intrinsic regulatory mechanism. However, in vitro transcribed mRNA, which encodes a proteolytically inactive Papp-a mutant, recues the papp-a knockdown phenotype as efficient as wild-type Papp-a. Thus, the developmental phenotype of papp-a knockdown is not a consequence of lacking Papp-a proteolytic activity. We conclude that Papp-a possesses biological functions independent of its proteolytic activity. Our data represent the first evidence for a non-proteolytic function of PAPP-A.
Original languageEnglish
JournalJournal of Biological Chemistry
Pages (from-to)9982-9992
Number of pages11
Publication statusPublished - Apr 2013

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