Placental-specific IGF-II is a major modulator of placental and fetal growth

Imprinted genes in mammals are expressed from only one of the parental chromosomes, and are crucial for placental development and fetal growth(1-4). The insulin-like growth factor II gene (Igf2) is paternally expressed in the fetus and placenta(5). Here we show that deletion from the Igf2 gene of a transcript (P0)(6,7) specifically expressed in the labyrinthine trophoblast of the placenta leads to reduced growth of the placenta, followed several days later by fetal growth restriction. The fetal to placental weight ratio is thus increased in the absence of the P0 transcript. We show that passive permeability for nutrients of the mutant placenta is decreased, but that secondary active placental amino acid transport is initially upregulated, compensating for the decrease in passive permeability. Later the compensation fails and fetal growth restriction ensues. Our study provides experimental evidence for imprinted gene action in the placenta that directly controls the supply of maternal nutrients to the fetus, and supports the genetic conflict theory of imprinting(8). We propose that the Igf2 gene, and perhaps other imprinted genes, control both the placental supply of, and the genetic demand for, maternal nutrients to the mammalian fetus.