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First published online February 18, 2004
doi: 10.1242/10.1242/dev.00997

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

¹ The Division of Endocrinology, Metabolism and Nutrition, Endocrine Research Unit, Mayo Clinic and Mayo Foundation, 200 First Street SW, Rochester, MN 55905, USA
² The University of Aarhus, Department of Molecular Biology, Science Park, Gustav Wieds Vej 10C, DK-8000, Aarhus C, Denmark
³ The Department of Pediatric and Adolescent Medicine, and Department of Biochemistry and Molecular Biology, Mayo Clinic and Mayo Foundation, 200 First Street SW, Rochester, MN 55905, USA

^* Author for correspondence (e-mail: conover.cheryl{at}mayo.edu)

Accepted 20 November 2003

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.

Key words: Pregnancy associated plasma protein A, Insulin-like growth factor, Gene targeting, Metalloproteinase

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