Placental-Specific Igf2 Deficiency Alters Developmental Adaptations to Undernutrition in Mice

Abstract

The pattern of fetal growth is a major determinant of the subsequent health of the infant. We recently showed in undernourished (UN) mice that fetal growth is maintained until late pregnancy, despite reduced placental weight, through adaptive up-regulation of placental nutrient transfer. Here, we determine the role of the placental-specific transcript of IGF-II (Igf2P0), a major regulator of placental transport capacity in mice, in adapting placental phenotype to UN. We compared the morphological and functional responses of the wild-type (WT) and Igf2P0-deficient placenta in WT mice fed ad libitium or 80% of the ad libitium intake. We observed that deletion of Igf2P0 prevented up-regulation of amino acid transfer normally seen in UN WT placenta. This was associated with a reduction in the proportion of the placenta dedicated to nutrient transport, the labyrinthine zone, and its constituent volume of trophoblast in Igf2P0-deficient placentas exposed to UN on d 16 of pregnancy. Additionally, Igf2P0-deficient placentas failed to up-regulate their expression of the amino acid transporter gene, Slc38a2, and down-regulate phosphoinositide 3-kinase-protein kinase B signaling in response to nutrient restriction on d 19. Furthermore, deleting Igf2P0 altered maternal concentrations of hormones (insulin and corticosterone) and metabolites (glucose) in both nutritional states. Therefore, Igf2P0 plays important roles in adapting placental nutrient transfer capacity during UN, via actions directly on the placenta and/or indirectly through the mother.

Intrauterine calorie restriction affects placental DNA methylation and gene expression

“…Another imprinted gene Igf2 serves as a fetal growth factor associated with fetal growth (14). In a study of Igf2P0 (placenta-specific knockout) mouse, a decrease in system A amino acid transport across the placenta was reported with fetal growth restriction (50). In our data we observed altered methylation patterns in exon 3 of Igf2 corresponding to a hypermethylated state in CR samples.…”

The placenta: a multifaceted, transient organ

“…Thus, if the surface area for exchange is reduced experimentally in mice, or the mother is subjected to undernutrition, placental expression of certain amino acid transporters is increased, enhancing the flux [27,28]. Full details of the signalling pathways involved are not available at present, although experimental data implicate placental Igf2 [29].…”

Maternal and fetal genomes interplay through phosphoinositol 3-kinase(PI3K)-p110α signaling to modify placental resource allocation

“…In adult tissues, the PI3K p110α isoform is primarily responsible for mediating the metabolic effects of insulin and insulinlike growth factors (IGFs), which are major feto-placental growth factors (11)(12)(13)(14). Altered placental PI3K signaling, particularly downstream of p110α, accompanies adaptations in placental phenotype when mismatches occur between maternal resource availability and the fetal genetic drive for growth during mouse development (15)(16)(17)(18). These findings suggest that p110α may be a critical sensor integrating the various signals involved in placental adaptation.…”