Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Characterization of the P0 mutation.
Figure 2: Growth kinetics during development.
Figure 3: Placental transfer is altered in P0 mutants.

Similar content being viewed by others

References

  1. Reik, W. & Walter, J. Genomic imprinting: parental influence on the genome. Nature Rev. Genet. 2, 21–32 (2001)

    Article  CAS  Google Scholar 

  2. Ferguson-Smith, A. C. & Surani, M. A. Imprinting and the epigenetic asymmetry between parental genomes. Science 293, 1086–1089 (2001)

    Article  CAS  Google Scholar 

  3. Sleutels, F., Barlow, D. P. & Lyle, R. The uniqueness of the imprinting mechanism. Curr. Opin. Genet. Dev. 10, 229–233 (2000)

    Article  CAS  Google Scholar 

  4. Tilghman, S. M. The sins of the fathers and mothers: genomic imprinting in mammalian development. Cell 96, 185–193 (1999)

    Article  CAS  Google Scholar 

  5. DeChiara, T. M., Robertson, E. J. & Efstratiadis, A. Parental imprinting of the mouse insulin-like growth factor II gene. Cell 64, 849–859 (1991)

    Article  CAS  Google Scholar 

  6. Moore, T. et al. Multiple imprinted sense and antisense transcripts, differential methylation and tandem repeats in a putative imprinting control region upstream of mouse Igf2. Proc. Natl Acad. Sci. USA 94, 12509–12514 (1997)

    Article  ADS  CAS  Google Scholar 

  7. Constância, M. et al. Deletion of a silencer element in Igf2 results in loss of imprinting independent of H19. Nature Genet. 26, 203–206 (2000)

    Article  Google Scholar 

  8. Moore, T. & Haig, D. Genomic imprinting in mammalian development: a parental tug-of-war. Trends Genet. 7, 45–49 (1991)

    Article  CAS  Google Scholar 

  9. Lefebvre, L. et al. Abnormal maternal behaviour and growth retardation associated with loss of the imprinted gene Mest. Nature Genet. 20, 163–169 (1998)

    Article  CAS  Google Scholar 

  10. Li, L. et al. Regulation of maternal behaviour and offspring growth by paternally expressed Peg3. Science 284, 330–333 (1999)

    Article  ADS  CAS  Google Scholar 

  11. Duvillie, B. et al. Phenotypic alterations in insulin-deficient mutant mice. Proc. Natl Acad. Sci. USA 94, 5137–5140 (1997)

    Article  ADS  CAS  Google Scholar 

  12. Wang, Z.-Q., Fung, M. R., Barlow, D. P. & Wagner, E. F. Regulation of embryonic growth and lysosomal targeting by the imprinted Igf2r/Mpr gene. Nature 372, 464–467 (1994)

    Article  ADS  CAS  Google Scholar 

  13. Lau, M. M. et al. Loss of imprinted IGF2/cation-independent mannose 6-phosphate receptor results in fetal overgrowth and perinatal lethality. Genes Dev. 8, 2953–2963 (1994)

    Article  CAS  Google Scholar 

  14. Leighton, P. A., Ingram, R. S., Eggenschwiler, J., Efstratiadis, A. & Tilghman, S. M. Disruption of imprinting caused by deletion of the H19 region in mice. Nature 375, 34–39 (1995)

    Article  ADS  CAS  Google Scholar 

  15. Sun, F. L., Dean, W. L., Kelsey, G., Allen, N. D. & Reik, W. Transactivation of Igf2 in a mouse model for Beckwith–Wiedemann syndrome. Nature 389, 809–815 (1997)

    Article  ADS  CAS  Google Scholar 

  16. Guillemot, F. et al. Genomic imprinting of Mash2, a mouse gene required for trophoblast development. Nature Genet. 9, 235–242 (1995)

    Article  CAS  Google Scholar 

  17. Georgiades, P., Watkins, M., Burton, G. J. & Ferguson-Smith, A. C. Roles for genomic imprinting and the zygotic genome in placental development. Proc. Natl Acad. Sci. USA 98, 4522–4527 (2001)

    Article  ADS  CAS  Google Scholar 

  18. Reik, W., Davies, K., Dean, W., Kelsey, G. & Constância, M. Imprinted genes and the coordination of fetal and postnatal growth in mammals. Novartis Found. Symp. 237, 19–31 (2001)

    CAS  PubMed  Google Scholar 

  19. Burns, J. L. & Hassan, A. B. Cell survival and proliferation are modified by insulin-like growth factor 2 between days 9 and 10 of mouse gestation. Development 128, 3819–3830 (2001)

    CAS  PubMed  Google Scholar 

  20. Gardner, R. L., Squire, S., Zaina, S., Hills, S. & Graham, C. F. Insulin-like growth factor-2 regulation of conceptus composition: effects of the trophoectoderm and inner cell mass genotypes in the mouse. Biol. Reprod. 60, 190–195 (1999)

    Article  CAS  Google Scholar 

  21. Baker, J., Liu, J.-P., Robertson, E. J. & Efstratiadis, A. Role of insulin-like growth factors in embryonic and postnatal growth. Cell 75, 73–82 (1993)

    Article  CAS  Google Scholar 

  22. Atkinson, D. E., Robinson, N. R. & Sibley, C. P. Development of the passive permeability characteristics of the rat placenta during the last third of gestation. Am. J. Physiol. 261, R1461–R1464 (1991)

    CAS  PubMed  Google Scholar 

  23. Johnson, L. W. & Smith, C. H. Neutral amino acid transport systems of microvillous membrane of human placenta. Am. J. Physiol. 251, C773–C780 (1988)

    Article  Google Scholar 

  24. Cramer, S., Beveridge, M., Kilberg, M. & Novak, D. Physiological importance of system A-mediated amino acid transport to rat fetal development. Am. J. Physiol. Cell. Physiol. 282, C153–C160 (2002)

    Article  CAS  Google Scholar 

  25. Newell, S., Ward, A. & Graham, C. Discriminating translation of insulin-like growth factor-II (IGF-II) during mouse embryogenesis. Mol. Reprod. Dev. 39, 249–258 (1994)

    Article  CAS  Google Scholar 

  26. Nielsen, J. et al. A family of insulin-like growth factor II mRNA-binding proteins represses translation in late development. Mol. Cell Biol. 19, 1262–1270 (1999)

    Article  CAS  Google Scholar 

  27. Godfrey, K. M. & Barker, D. J. Fetal programming and adult health. Public Health Nutr. 4, 611–624 (2001)

    Article  CAS  Google Scholar 

  28. Ozanne, S. E. & Hales, C. N. The long-term consequences of intra-uterine protein malnutrition for glucose metabolism. Proc. Nutr. Soc. 58, 615–619 (1999)

    Article  CAS  Google Scholar 

  29. Adam, G. I., Cui, H., Miller, S. J., Flam, F. & Ohlsson, R. Allele-specific in situ hybridization (ASISH) analysis: a novel technique which resolves differential allelic usage of H19 within the same cell lineage during human placental development. Development 122, 839–847 (1996)

    CAS  PubMed  Google Scholar 

  30. Hill, D. J. Relative abundance and molecular size of immunoreactive insulin-like growth factors I and II in human fetal tissues. Early Hum. Dev. 21, 49–58 (1990)

    Article  CAS  Google Scholar 

Download references

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

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Miguel Constância or Wolf Reik.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Constância, M., Hemberger, M., Hughes, J. et al. Placental-specific IGF-II is a major modulator of placental and fetal growth. Nature 417, 945–948 (2002). https://doi.org/10.1038/nature00819

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature00819

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing