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

Naturevolume 417pages945948 (2002) | Download Citation

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Abstract

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.

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Acknowledgements

We dedicate this paper to Francesca Stewart who died in December 2000 and who was instrumental in initiating this collaborative work. We thank D. Hill for help with IGF-II serum assays, E. Walters for help with the statistical analyses, T. Moore for discussions, and C. Graham for suggestions on the manuscript. Our work is supported by the Medical Research Council (MRC) and the Biotechnology and Biological Sciences Research Council (BBSRC). G.K. is a Senior Fellow of the MRC.

Author information

Affiliations

  1. Laboratory of Developmental Genetics and Imprinting, Developmental Genetics Programme, The Babraham Institute, Cambridge, CB2 4AT, UK

    • Miguel Constância
    • , Jennifer Hughes
    • , Wendy Dean
    • , Francesca Stewart
    • , Gavin Kelsey
    •  & Wolf Reik
  2. Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, T2N 4N1, Canada

    • Myriam Hemberger
  3. Department of Anatomy, University of Cambridge, Cambridge, CB2 3DY, UK

    • Anne Ferguson-Smith
  4. Max-Planck-Institut für Molekulare Genetik, D-14195, Berlin-Dahlem, Germany

    • Reinald Fundele
  5. The Physiological Laboratory, University of Cambridge, Cambridge, CB2 3EG, UK

    • Abigail Fowden
  6. Academic Unit of Child Health, The University of Manchester, St Mary's Hospital, Manchester, M13 0JH, UK

    • Colin Sibley

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The authors declare that they have no competing financial interests.

Corresponding authors

Correspondence to Miguel Constância or Wolf Reik.

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https://doi.org/10.1038/nature00819

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