Placental adaptations to the maternal–fetal environment: implications for fetal growth and developmental programming  Ionel Sandovici, Katharina Hoelle, Emily Angiolini, Miguel Constância  Reproductive BioMedicine Online  Volume 25, Issue 1, Pages 68-89 (July 2012) DOI: 10.1016/j.rbmo.2012.03.017 Copyright © 2012 Reproductive Healthcare Ltd. Terms and Conditions

Figure 1 Mouse genetic models of mismatched placental supply and fetal demand, based on Igf2 manipulations. The Igf2P0+/− is a model of decreased placental supply with normal fetal demand. Deletion of the placental-specific Igf2P0 creates a small placenta that adapts to fetal growth demands by increasing nutrient transport; these functional adaptations are unable to fully compensate for the loss in surface area for exchange and the Igf2P0 fetuses eventually become growth restricted at the end of gestation. In Igf2+/− total null, the levels of fetal demand and placental supply are decreased by deleting Igf2 in both compartments. In late gestation, the lower rate of cell proliferation and growth of the Igf2-deficient fetus leads to signalling of reduced demand to the placenta, which results in decreased nutrient transport. The H19Δ13−/+ is a model of increased fetal demand and placental supply due to excess of Igf2 in both compartments. The placental supply however exceeds fetal demand and the fetal–placental signalling of this mismatch is proposed to result in decreased nutrient transport. Maternal constraint signals may also be at play. All the models presented above are paradigm examples of adaptive responses caused by a developmentally regulated mismatch between placental and fetal size. Reproductive BioMedicine Online 2012 25, 68-89DOI: (10.1016/j.rbmo.2012.03.017) Copyright © 2012 Reproductive Healthcare Ltd. Terms and Conditions

Figure 2 Transporter-mediated nutrient transfer across the human syncytiotrophoblast – see details in the text. (A) Glucose transport. (B) Transporters involved in the exchange of small neural amino acids, applicable for serine and alanine. (C) Fatty acid transport. (D) Folic acid transport. (E) Calcium transport. (F) Iron transport. AA=amino acids; BM=basal membrane; FA=fatty acid; MVM=microvillus membrane; Sy=syncytiotrophoblast; TF=transferrin. Reproductive BioMedicine Online 2012 25, 68-89DOI: (10.1016/j.rbmo.2012.03.017) Copyright © 2012 Reproductive Healthcare Ltd. Terms and Conditions

Figure 3 Roles of imprinted genes in controlling endocrine function of the murine placenta. There are numerous hormones produced and secreted by the placenta, which include but are not limited to prolactin-like proteins, growth hormone, corticotrophin-releasing hormone, prostaglandins, leptin and insulin-like growth factors. These hormones play diverse biological roles and can affect the fetal supply of nutrients and oxygen either directly or indirectly, and may stretch beyond the period of in-utero growth via effects on maternal care, maternal appetite and mammary growth. Secretory products of the decidua basalis (Db), and of spongiotrophoblast cells and trophoblast giant cells (TGC) within the junctional zone (Jz) are particularly abundant in maternal circulation throughout gestation. The development of sinusoidal trophoblast giant cells (S-TGC) within the labyrinthine zone (Lz) may facilitate hormone/cytokine delivery into the fetal compartment. Paternally expressed genes (blue) promote (+) fetal and placental growth. Within the placenta these genes are suggested to positively regulate the endocrine output of the placenta, thus conferring greater nutrient availability to offspring in utero and post natally (e.g. via placental prolactin growth hormone-related gene systems). Maternally expressed genes (red) suppress (−) fetal and placental growth and are suggested to limit endocrine output, reducing diversion of maternal resources via decreased secretion of metabolically active hormones that control nutrient availability. The placental expression patterns and developmental functions of the genes illustrated in this figure have been reviewed (Coan et al., 2005b; Fowden et al., 2006, 2011; Lefebvre, 2012). Information on Slc38a4 taken from an International Federation of Placenta Associations meeting abstract (Angiolini et al., 2009). In addition, loss-of-function studies in mice show that the selected genes are negative or positive regulators of placental growth/differentiation (reviewed by Fowden et al., 2011). Some of the genes that encode placental hormones may themselves be regulated by genomic imprinting as shown to be the case in deer mice (for Pl1-v). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) Reproductive BioMedicine Online 2012 25, 68-89DOI: (10.1016/j.rbmo.2012.03.017) Copyright © 2012 Reproductive Healthcare Ltd. Terms and Conditions