The latest stages of mammalian gestation entail an accelerated growth phase, which is critical for optimal neonatal birth weight and preparedness for life outside the womb. While it is apparent that the fuel source for this massive growth spurt is circulating maternal metabolites, it is less clear whether placental storage of metabolic fuels is essential for this process. Insights into this process emerge from our studies of the nuclear receptor PPARy, an essential regulator of placental development and metabolism. We found that the placenta-enriched transcription cofactor LCoR (Ligand-dependent CoRepressor) is a coactivator (Not a corepressor) of PPARy, on the target gene Mud both in vitro and in vivo. Molecular genetic analyses revealed that LCoR-deficient neonates die within hours of birth. These neonates do not exhibit obvious anatomic anomalies, but display limp forelimbs, lethargy, and failure to suckle. Importantly, while exhibiting normal growth until mid- gestation, Lcor-null embryos are significantly growth-restricted at term, alongside significant enlargement of the placenta. Histological analyses reveal that Lcor-null placentas retain a substantially higher number of placental glycogen trophoblasts (GlyT) compared to their WT counterparts, providing a plausible explanation to their larger mass. Importantiy, both PPARy, and LCoR are critical for placental expression of the glucagon receptor gene, Gcgr, suggesting that Lcor-null placentas accumulate glycogen due to failure to respond to the glycogenolytic signal of glucagon. Our findings suggest that LCoR regulates export of glycogen-derived fuel from placental GlyT to the embryo, and that its loss restricts the growth of the late fetus by limiting its access to this fuel. We further surmise that this severe deprivation of placental fuel sources at the last stages of gestation underlies the fatal, lethargic state of Lcor-null neonates. Accordingly, our overarching hypothesis is that transcriptional and developmental regulation of placental glycogen stores plays an essential role in late embryonic growth and neonatal survival.
Three specific aims driven by this hypothesis will dissect the role and regulation of placental glycogen stores in late embryogenesis:
Aim 1. Determine the outcomes of glycogen trophoblast ablation.
Aim 2. Define the lineage-specific funcfions of LCoR in the placenta and the embryo.
Aim 3. Dissect the molecular mechanisms of placental gene regulation by LCoR and PPARy.

Public Health Relevance

Growth restriction, stillbirth, neonatal mortality and infant morbidity due to gestational problems are a serious public health issue. This project will fill major knowledge gaps in this area by defining novel transcriptional and developmental mechanisms that regulate key fuel storage and metabolism processes in the placenta that affect the maturation and survival of the embryo and neonate.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
1P01HD069316-01A1
Application #
8346036
Study Section
Special Emphasis Panel (ZHD1-DSR-Z (52))
Project Start
Project End
Budget Start
2012-06-15
Budget End
2013-02-28
Support Year
1
Fiscal Year
2012
Total Cost
$256,489
Indirect Cost
$28,538
Name
Magee-Women's Research Institute and Foundation
Department
Type
DUNS #
119132785
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Shaffer, Ben; McGraw, Serge; Xiao, Siyu C et al. (2015) The DNMT1 intrinsically disordered domain regulates genomic methylation during development. Genetics 199:533-41
Larkin, J C; Sears, S B; Sadovsky, Y (2014) The influence of ligand-activated LXR on primary human trophoblasts. Placenta 35:919-24
Larkin, Jacob; Chen, Baosheng; Shi, Xiao-Hua et al. (2014) NDRG1 deficiency attenuates fetal growth and the intrauterine response to hypoxic injury. Endocrinology 155:1099-106
Mohammadyani, Dariush; Tyurin, Vladimir A; O'Brien, Matthew et al. (2014) Molecular speciation and dynamics of oxidized triacylglycerols in lipid droplets: Mass spectrometry and coarse-grained simulations. Free Radic Biol Med 76:53-60
Makkar, A; Mishima, T; Chang, G et al. (2014) Fatty acid binding protein-4 is expressed in the mouse placental labyrinth, yet is dispensable for placental triglyceride accumulation and fetal growth. Placenta 35:802-7