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

Kasper Kjaer-Sorensen, Ditte H. Engholm, Hiroyasu Kamei, Maria G. Morch, Anisette O. Kristensen, Jianfeng Zhou, Cheryl A. Conover, Cunming Duan, Claus Oxvig

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Pregnancy-associated plasma protein-A (PAPP-A) is a large metalloproteinase specifically cleaving insulin-like growth factor (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 of the Igf system. Biochemical analysis of recombinant zebrafish Papp-a demonstrates conservation of proteolytic activity, specificity, and the intrinsic regulatory mechanism. However, in vitro transcribed mRNA, which encodes a proteolytically inactive Papp-a mutant, recues the papp-a knockdown phenotype as efficiently as wildtype Papp-a. Thus, the developmental phenotype of papp-a knockdown is not a consequence of lacking Papp-a proteolytic activity.Weconclude 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 (US)
Pages (from-to)9982-9992
Number of pages11
JournalJournal of Biological Chemistry
Volume288
Issue number14
DOIs
StatePublished - Apr 5 2013

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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