ABSTRACT
Imprinting control region (ICR1) controls the expression of the Igf2 and H19 genes in a parent-of-origin specific manner. Appropriate expression of the Igf2-H19 locus is fundamental for normal fetal development, yet the importance of ICR1 in the placental production of hormones that promote maternal nutrient allocation to the fetus is unknown. To address this, we used a novel mouse model to selectively delete ICR1 in the endocrine junctional zone (Jz) of the mouse placenta (Jz-ΔICR1). The Jz-ΔICR1 mice exhibit increased Igf2 and decreased H19 expression specifically in the Jz. This was accompanied by an expansion of Jz endocrine cell types due to enhanced rates of proliferation and increased expression of pregnancy-specific glycoprotein 23 in the placenta of both fetal sexes. However, changes in the endocrine phenotype of the placenta were related to sexually-dimorphic alterations to the abundance of Igf2 receptors and downstream signalling pathways (Pi3k-Akt and Mapk). There was no effect of Jz-ΔICR1 on the expression of targets of the H19-embedded miR-675 or on fetal weight. Our results demonstrate that ICR1 controls placental endocrine capacity via sex-dependent changes in signalling.
Subject(s)
Endocrine Glands/metabolism , Insulin-Like Growth Factor II/genetics , Locus Control Region , Placenta/metabolism , RNA, Long Noncoding/genetics , Signal Transduction , Animals , Female , Genetic Loci , Genomic Imprinting , Glycoproteins/genetics , Glycoproteins/metabolism , Insulin-Like Growth Factor II/metabolism , Male , Mice , Mice, Inbred C57BL , Phosphatidylinositol 3-Kinases/metabolism , Pregnancy , Pregnancy Proteins/genetics , Pregnancy Proteins/metabolism , Proto-Oncogene Proteins c-akt/metabolism , RNA, Long Noncoding/metabolismABSTRACT
The placenta regulates materno-fetal nutrient transfer and secretes hormones that enable maternal physiological support of the pregnancy. In mice, these functions are performed by the labyrinth (Lz) and junctional (Jz) zones, respectively. Insulin-like growth factor 2 (Igf2) is an imprinted gene expressed by the conceptus that is important for promoting fetal growth and placenta formation. However, the specific role of Igf2 in the Jz in regulating placental endocrine function and fetal development is unknown. This study used a novel model to investigate the effect of conditional loss of Igf2 in the Jz (Jz-Igf2UE) on placental endocrine cell formation and the expression of hormones and IGF signaling components in placentas from female and male fetuses. Jz-Igf2UE altered gross placental structure and expression of key endocrine and signaling genes in a sexually dimorphic manner. The volumes of spongiotrophoblast and glycogen trophoblast in the Jz were decreased in placentas from female but not male fetuses. Expression of insulin receptor was increased and expression the MAPK pathway genes (Mek1, P38α) decreased in the placental Jz of female but not male fetuses. In contrast, expression of the type-1 and -2 IGF receptors and the MAPK pathway genes (H-ras, N-ras, K-ras) was decreased in the placental Jz from male but not female fetuses. Expression of the steroidogenic gene, Cyp17a1, was increased and placental lactogen-2 was decreased in the placenta of both sexes. In summary, we report that Jz-Igf2UE alters the cellular composition, IGF signaling components and hormone expression of the placental Jz in a manner largely dependent on fetal sex.