Abstract
BackgroundPregnancy-associated plasma protein A2 (PAPPA2) is an insulin-like growth factor binding protein (IGFBP) protease expressed in the placenta and upregulated in pregnancies complicated by pre-eclampsia. The mechanism linking PAPPA2 expression and pre-eclampsia and the consequences of altered PAPPA2 expression remain unknown. We previously identified PAPPA2 as a candidate gene for a quantitative trait locus (QTL) affecting growth in mice and in the present study examined whether this QTL affects placental PAPPA2 expression and, in turn, placental or embryonic growth.MethodsUsing a line of mice that are genetically homogenous apart from a 1 megabase QTL region containing the PAPPA2 gene, we bred mice homozygous for alternate QTL genotypes and collected and weighed placentae and embryos at E12.5. We used quantitative RT-PCR to measure the mRNA levels of PAPPA2, as well as mRNA levels of IGFBP-5 (PAPPA2's substrate), and PAPPA (a closely related IGFBP protease) to examine potential feedback and compensation effects. Western blotting was used to quantify PAPPA2 protein. Birth weight was measured in pregnancies allowed to proceed to parturition.ResultsPAPPA2 mRNA and protein expression levels in the placenta differed by a factor of 2.5 between genotypes, but we did not find a significant difference between genotypes in embryonic PAPPA2 mRNA levels. Placental IGFBP-5 and PAPPA mRNA expression levels were not altered in response to PAPPA2 levels, and we could not detect IGFBP-5 protein in the placenta by Western blotting. The observed difference in placental PAPPA2 expression had no significant effect on placental or embryonic mass at mid-gestation, birth weight or litter size.ConclusionsDespite a significant difference between genotypes in placental PAPPA2 expression similar in magnitude to the difference between pre-eclamptic and normal placentae previously reported, we observed no difference in embryonic, placental or birth weight. Our results suggest that elevated PAPPA2 levels are a consequence, rather than a cause, of pregnancy complications.
Highlights
Pregnancy-associated plasma protein A2 (PAPPA2) is an insulin-like growth factor binding protein (IGFBP) protease expressed in the placenta and upregulated in pregnancies complicated by pre-eclampsia
We examined natural variation in the PAPPA2 gene that has previously been associated with postnatal growth in mice: quantitative trait locus (QTL) mapping revealed that a chromosomal region containing the PAPPA2 gene affects body size [24]
Placental gene expression We examined the expression of PAPPA2, its substrate (IGFBP5) and a closely related gene (PAPPA) at 12.5 days post-coitum in mice that differ in genotype at the 1 MB
Summary
Pregnancy-associated plasma protein A2 (PAPPA2) is an insulin-like growth factor binding protein (IGFBP) protease expressed in the placenta and upregulated in pregnancies complicated by pre-eclampsia. Four other studies have found PAPPA2 to be upregulated in placentae from pregnancies complicated by pre-eclampsia and a pre-eclampsia-like syndrome, HELLP (Hemolytic anemia, Elevated Liver enzymes, and Low Platelet count) [17,18,19,20]. It is not clear whether PAPPA2 expression is upregulated to compensate for abnormal placentation or whether elevated PAPPA2 levels cause abnormal placental development, leading to hypertensive disorders [21]. Recent work has shown that PAPPA2 is expressed at high levels in the murine placenta and that it is expressed in along the fetal-maternal interface of the placenta in both mouse and human [23], suggesting that the mouse may be a suitable model for studying the placental roles of PAPPA2
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