Metalloproteinase pregnancy-associated plasma protein A is a critical growth regulatory factor during fetal development

Cheryl A. Conover, Laurie K. Bale, Michael T. Overgaard, Edward W. Johnstone, Ulla L. Laursen, Ernst Martin Füchtbauer, Claus Oxvig, Jan van Deursen

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201 Scopus citations

Abstract

Pregnancy-associated plasma protein A (PAPPA) is a metzincin superfamily metalloproteinase in the insulin-like growth factor (IGF) system. PAPPA increases IGF bioavailability and mitogenic effectiveness in vitro through regulated cleavage of IGF-binding protein 4 (IGFBP4). To determine its function in vivo, we generated PAPPA-null mice by gene targeting. Mice homozygous for targeted disruption of the PAPPA gene were viable but 60% the size of wild-type littermates at birth. The impact of the mutation was exerted during the early embryonic period prior to organogenesis, resulting in proportional dwarfism. PAPPA, IGF2 and IGFBP4 transcripts co-localized in wild-type embryos, and expression of IGF2 and IGFBP4 mRNA was not altered in PAPPA-deficient embryos. However, IGFBP4 proteolytic activity was completely lacking in fibroblasts derived from PAPPA-deficient embryos, and IGFBP4 effectively inhibited IGF-stimulated mitogenesis in these cells. These results provide the first direct evidence that PAPPA is an essential growth regulatory factor in vivo, and suggest a novel mechanism for regulated IGF bioavailability during early fetal development.

Original languageEnglish (US)
Pages (from-to)1187-1194
Number of pages8
JournalDevelopment
Volume131
Issue number5
DOIs
StatePublished - Mar 1 2004

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Keywords

  • Gene targeting
  • Insulin-like growth factor
  • Metalloproteinase
  • Pregnancy associated plasma protein A

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

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