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Transactivation of Igf2 in a mouse model of Beckwith–Wiedemann syndrome

Nature volume 389, pages 809–815 (1997)Cite this article

Abstract

The gene IGF2, which encodes a fetal insulin-like growth factor, is imprinted, so only one of two parental copies of the gene is expressed. The altered expression of IGF2 has been implicated in Beckwith–Wiedemann syndrome, a human fetal overgrowth syndrome, which is characterized by overgrowth of several organs and an increased risk of developing childhood tumours. We have introduced Igf2 transgenes into the mouse genome by using embryonic stem cells, which leads to transactivation of the endogenous Igf2 gene. The consequent overexpression of Igf2 results in most of the symptoms of Beckwith–Wiedemann syndrome, including prenatal overgrowth, polyhydramnios, fetal and neonatal lethality, disproportionate organ overgrowth including tongue enlargement, and skeletal abnormalities. These phenotypes establish Igf2 overexpression as a key determinant of Beckwith–Wiedemann syndrome.

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Figure 1: Introduction and expression of Igf2 transgene construct in ES cells.
Figure 2: Fetal and postnatal overgrowth in transgenic chimaeras.
Figure 3: Disproportionate organ overgrowth in transgenic chimaeras.
Figure 4: Overexpression of Igf2 mRNA in transgenic chimaeras.
Figure 5: RNase protection assays to distinguish transgenic and endogenous Igf2 transcripts.
Figure 6: Methylation of DMR2 in transgenic and endogenous Igf2.

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Acknowledgements

We thank D. Brown, J. Walter, J. Oswald, E. Maher, D. Hill, S. Fleming, J. Pell, A. Murrell and E. Grau for help and advice, and D. Styles, L. Notton and D. Powell for the preparation of manuscript and figures. This work is supported by Action Research, BBSRC, MRC and MAFF. G.K. is a senior fellow of the MRC.

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Author notes

  1. Fang-Lin Sun

    Present address: Department of Biology, Washington University, Campus Box 1229, St Louis, Missouri, 63130-4899, USA

Authors and Affiliations

  1. Laboratory of Developmental Genetics and Imprinting, Cambridge, CB2 4AT, UK

    Fang-Lin Sun, Wendy L. Dean, Gavin Kelsey & Wolf Reik

  2. Department of Development and Genetics, Laboratory of Developmental Neurobiology, The Babraham Institute, Cambridge, CB2 4AT, UK

    Nicholas D. Allen

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Correspondence to Wolf Reik.

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Sun, FL., Dean, W., Kelsey, G. et al. Transactivation of Igf2 in a mouse model of Beckwith–Wiedemann syndrome. Nature 389, 809–815 (1997). https://doi.org/10.1038/39797

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