title: Developmental adaptations to increased fetal nutrient demand in mouse genetic models of Igf2-mediated overgrowth.
abstract: The healthy development of the fetus depends on an optimal balance between fetal genetic drive for growth and the maternal ability to provide nutrients through the placenta. Nothing is known about fetal-placental signaling in response to increased fetal demand in the situation of overgrowth. Here, we examined this question using the H19(Δ13) mouse model, shown previously to result in elevated levels of Igf2. Fetal and placental weights in H19(Δ13) were increased by 23% and 45%, respectively, at E19, when compared with wild-type mice. Unexpectedly, we found that disproportionately large H19(Δ13) placentas transport 20-35% less (per gram placenta) glucose and system A amino acids and have similar reductions in passive permeability, despite a significantly greater surface area for nutrient exchange and theoretical diffusion capacity compared with wild-type mice. Expression of key transporter genes Slc2a3 and Slc38a4 was reduced by ∼20%. Decreasing the overgrowth of the H19(Δ13) placenta by genetically reducing levels of Igf2P0 resulted in up-regulation of system A activity and maintenance of fetal overgrowth. Our results provide direct evidence that large placentas can modify their nutrient transfer capacity to regulate fetal nutrient acquisition. Our findings are indicative of fetal-placental signaling mechanisms that limit total demand for maternal nutrients.
authors.affiliation: Laboratory of Developmental Genetics and Imprinting, The Babraham Institute, Babraham Research Campus, Cambridge, UK.
authors.forename: Emily
authors.initials: E
authors.lastname: Angiolini
authors.forename: Phillip M
authors.initials: PM
authors.lastname: Coan
authors.forename: Ionel
authors.initials: I
authors.lastname: Sandovici
authors.forename: O H
authors.initials: OH
authors.lastname: Iwajomo
authors.forename: Gerrard
authors.initials: G
authors.lastname: Peck
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Burton
authors.forename: Colin P
authors.initials: CP
authors.lastname: Sibley
authors.forename: Wolf
authors.initials: W
authors.lastname: Reik
authors.forename: Abigail L
authors.initials: AL
authors.lastname: Fowden
authors.forename: Miguel
authors.initials: M
authors.lastname: Constância
mesh_terms: D000818:Animals; D005260:Female; D047109:Fetal Development / Q000235:genetics / Q000502:physiology; D005333:Fetus / Q000378:metabolism*; D005838:Genotype; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics
chemical_list: C094335:H19 long non-coding RNA; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D007335:Insulin-Like Growth Factor II