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

Abstract

Imprinted genes in mammals are expressed from only one of the parental chromosomes, and are crucial for placental development and fetal growth. The insulin-like growth factor II gene (Igf2) is paternally expressed in the fetus and placenta. Here we show that deletion from the Igf2 gene of a transcript (P0) 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. 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.

Fetal growth restriction: a workshop report

“…In murine models, most of the 60 recognized imprinted genes are expressed during fetal life and, in particular, in the placenta, in which they may regulate fetal demand and maternal supply of nutrients. This peculiar mechanism of growth regulation has been demonstrated for Igf2 in mice lacking specific Igf2 placental transcript [3].…”

“…ESX1 mutants show changes of vascularization in the placental labyrinth [8], Igf2 null mice have an inefficient placental transport [3], and p57/Kip2-deficient mice present changes of labyrinth and spongiotrophoblast [9]. Data from murine models strongly indicate that IUGR cannot be considered a disease per se, rather a manifestation of many possible fetal gene defects that primarily affect placental development and function.…”

“…While the knowledge of IUGR resulting from a shallow trophoblast invasion during the first trimester, together with Doppler studies showing changes in the utero-placental circulation, is widespread among both clinicians and scientists, the discoveries that the nutrient supply can also be decreased by changes in the placental transport properties is not so well known. Moreover, recent studies in a number of mouse knockout and transgenic models have allowed to link defects in imprinted genes to changes in specific transport systems [3]. However, the lessons of the murine experiments need to be compared to results obtained in human pregnancies.…”

IGF2: Epigenetic regulation and role in development and disease

“…Igf2 is widely expressed during murine embryonic development and is particularly important in placental growth [18]. As with many genes that regulate placental development, Igf2 is imprinted, or expressed monoallelically, and active only on the paternally inherited allele.…”

Placental 5-methylcytosine and 5-hydroxymethylcytosine patterns associate with size at birth

“…[4][5][6][7] In addition, altered placental expression of imprinted genes has been reported in association with human fetal growth restriction. [8][9][10] The imprinted insulin-like growth factor 2 (IGF2) gene has a major role in the matching of placental nutrient supply to fetal demand, 4 and altered IGF2 expression has been reported in association with fetal growth restriction in humans. 9,10 IGF2, and the neighboring H19 gene, are situated in an imprinted gene cluster on human chromosome 11p15.…”