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Letters to Nature

Nature 417, 945-948 (27 June 2002) | doi:10.1038/nature00819; Received 22 January 2002; Accepted 3 May 2002

Placental-specific IGF-II is a major modulator of placental and fetal growth

Miguel Constância1, Myriam Hemberger2, Jennifer Hughes1, Wendy Dean1, Anne Ferguson-Smith3, Reinald Fundele4, Francesca Stewart1, Gavin Kelsey1, Abigail Fowden5, Colin Sibley6 & Wolf Reik1

  1. Laboratory of Developmental Genetics and Imprinting, Developmental Genetics Programme, The Babraham Institute, Cambridge CB2 4AT, UK
  2. Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta T2N 4N1, Canada
  3. Department of Anatomy, University of Cambridge, Cambridge CB2 3DY, UK
  4. Max-Planck-Institut für Molekulare Genetik, D-14195 Berlin-Dahlem, Germany
  5. The Physiological Laboratory, University of Cambridge, Cambridge CB2 3EG, UK
  6. Academic Unit of Child Health, The University of Manchester, St Mary's Hospital, Manchester M13 0JH, UK

Correspondence to: Miguel Constância1Wolf Reik1 Correspondence and requests for materials should be addressed to M.C. (e-mail: Email: miguel.constancia@bbsrc.ac.uk) or W.R. (e-mail: Email: wolf.reik@bbsrc.ac.uk).

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Imprinted genes in mammals are expressed from only one of the parental chromosomes, and are crucial for placental development and fetal growth1, 2, 3, 4. The insulin-like growth factor II gene (Igf2) is paternally expressed in the fetus and placenta5. Here we show that deletion from the Igf2 gene of a transcript (P0)6, 7 specifically expressed in the labyrinthine trophoblast of the placenta leads to reduced growth of the placenta, followed several days later by fetal growth restriction. The fetal to placental weight ratio is thus increased in the absence of the P0 transcript. We show that passive permeability for nutrients of the mutant placenta is decreased, but that secondary active placental amino acid transport is initially upregulated, compensating for the decrease in passive permeability. Later the compensation fails and fetal growth restriction ensues. Our study provides experimental evidence for imprinted gene action in the placenta that directly controls the supply of maternal nutrients to the fetus, and supports the genetic conflict theory of imprinting8. We propose that the Igf2 gene, and perhaps other imprinted genes, control both the placental supply of, and the genetic demand for, maternal nutrients to the mammalian fetus.