Regulation of supply and demand for maternal nutrients in mammals by imprinted genes

Abstract

The placenta has evolved in eutherian mammals primarily to provide nutrients for the developing fetus. The genetic control of the regulation of supply and demand for maternal nutrients is not understood. In this review we argue that imprinted genes have central roles in controlling both the fetal demand for, and the placental supply of, maternal nutrients. Recent studies on Igf2 (insulin-like growth factor 2) knockout mouse models provide experimental support for this hypothesis. These show effects on placental transport capacity consistent with a role of IGF-II in modulating both the placental supply and fetal demand for nutrients. Imprinting of genes with such functions may have coevolved with the placenta and new evidence suggests that transporter proteins, as well as the regulators themselves, may also be imprinted. These data and hypotheses are important, as deregulation of supply and demand affects fetal growth and has long term consequences for health in mammals both in the neonatal period and, as a result of fetal programming, in adulthood.

Figure 1. Placental development in the mouse

Early development of the mouse embryo from embryonic day (E) 4 - E13, showing the origins of the extra-embryonic lineages and the components of the placenta. ICM, inner cell mass. (After Rossant & Cross, 2001.)

Figure 2. Proposed functions of imprinted supply and demand genes in the distal chromosome 7 cluster in the mouse

The cluster contains a positive regulator of supply and demand for maternal nutrients (+ sign and large arrows), the paternally expressed Igf2 gene. We propose that most of the genes in the cluster that are maternally expressed counteract negatively the dominant signals from IGF-II by reducing the supply of nutrients by the placenta (- sign and small arrows). A negative effect of the maternally expressed genes on nutrient demand by the fetus cannot be excluded (not represented). This functional antagonism may or may not involve a direct interaction with the Igf2 gene product. The genes represented here are expressed and imprinted in the placenta. The positive effects on supply and demand are controlled by paternal germ line epigenetic modifications at Imprinting Centre 1 (IC1) and balanced by the negative effects on supply controlled by maternal germ line epigenetic modifications at IC2. Note that not all of the genes within the imprinted cluster are represented. The genes shown here are: Obph1 (oxysterol-binding protein), Nap1l4 (nucleosome assembly protein), Ipl (cytoplasmic protein with a pleckstrin-homology domain), Slc22a1l (organic cation transporter), Cdkn1c (cyclin-dependent kinase inhibitor), Kcnq1 (voltage-gated potassium channel protein KQT-like1), Tssc4 (tumor-suppressing subchromosomal transferable fragment 4), Tapa1 (CD81 antigen), Mash2 (BHLH transcription factor), Igf2 (insulin-like growth factor). Red: maternally expressed genes; Blue: paternally expressed genes.