| First Author | Conover CA | Year | 2004 |
| Journal | Development | Volume | 131 |
| Issue | 5 | Pages | 1187-94 |
| PubMed ID | 14973274 | Mgi Jnum | J:88578 |
| Mgi Id | MGI:3034154 | Doi | 10.1242/dev.00997 |
| Citation | Conover CA, et al. (2004) Metalloproteinase pregnancy-associated plasma protein A is a critical growth regulatory factor during fetal development. Development 131(5):1187-94 |
| abstractText | 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. |
