Adaptation of nutrient supply to fetal demand in the mouse involves interaction between the Igf2 gene and placental transporter systems

Abstract

The mammalian fetus is unique in its dependence during gestation on the supply of maternal nutrients through the placenta. Maternal supply and fetal demand for nutrients need to be fine tuned for healthy growth and development of the fetus along its genetic trajectory. An altered balance between supply and demand can lead to deviations from this trajectory with long-term consequences for health. We have previously shown that in a knockout lacking the imprinted placental-specific Igf2 transcript (P0), growth of the placenta is compromised from early gestation but fetal growth is normal until late gestation, suggesting functional adaptation of the placenta to meet the fetal demands. Here, we show that placental transport of glucose and amino acids are increased in the Igf2 P0(+/-) null and that this up-regulation of transport occurs, at least in part, through increased expression of the transporter genes Slc2a3 and Slc38a4, the imprinted member of the System A amino acid transporter gene family. Decreasing fetal demand genetically by removal of fetal Igf2 abolished up-regulation of both transport systems and reduced placental System A amino acid transport activity and expression of Slc38a2 in late gestation. Our results provide direct evidence that the placenta can respond to fetal demand signals through regulation of expression of specific placental transport systems. Thus, crosstalk between an imprinted growth demand gene (Igf2) and placental supply transporter genes (Slc38a4, Slc38a2, and Slc2a3) may be a component of the genetic control of nutrient supply and demand during mammalian development.

Fig. 1.

The effects of deletion of either the Igf2 P0 transcript from the labyrinthine trophoblast alone (A and B, Igf2 P0^+/-)orthe Igf2 gene from all feto-placental tissues (C and D, Igf2 null^+/-) on the placental transfer of ¹⁴C-glucose (A and C) and ¹⁴C-MeAIB (B and D), calculated as a ratio of mutant to wild-type transfer expressed either per gram of placenta or per gram of fetus at two gestational ages (E16 and E19). Ratios >1 indicate increased transfer by the mutant placenta, whereas ratios <1 indicate reduced transfer by the mutant placenta with respect to either placental or fetal weight. Bars indicate 95% confidence limits. *, P < 0.05; **, P < 0.01; ***, P < 0.001 significantly different from 1.

Fig. 2.

Expression analysis of the glucose transporters Slc2a1 and Slc2a3 by Northern blotting in Igf2 P0^+/- placentas at E16. Graphs of the mean expression levels are shown with the wild-type levels normalized to 1, together with representative Slc2a3 Northern blots of total RNA obtained from wild-type (WT) and Igf2 P0^+/- placentas (P0). Bars indicate SE. WT^+/+, n = 12; P0^+/-, n = 12 for Slc2a3; n = 7 for both groups for Slc2a1. **, P < 0.01.

Fig. 3.

Expression analysis of System A amino acid transporter genes (Slc38a1, Slc38a2, and Slc38a4) by Northern blotting in Igf2 P0^+/- (A) and Igf2 null^+/- (B) placentas compared to their wild-types (WT) at two gestational ages (E16 and E19, n = 7 for all WT and mutant groups). Graphs of mean expression levels are shown with the wild-type levels normalized to 1 together with representative Northern blots of total RNA obtained from wild-type (WT) and mutant placentas for Slc38a4 (A), at E16 and E19 and Slc38a2 (B), at E19, compared to Gapd loading. Bars indicate SE. ***, P < 0.001; **, P < 0.01 significantly different from the value in the wild-type. Note increase in signal in the Igf2 P0^+/- when compared to WT for the 4-kb transcript only at E16 but not E19.