Perturbations to the IGF1 growth pathway and adult energy homeostasis following disruption of mouse chromosome 12 imprinting

Authors

  • M. Charalambous,

    1. Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
    Current affiliation:
    1. Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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  • S. T. da Rocha,

    1. Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
    Current affiliation:
    1. Mammalian Developmental Epigenetics Group, Unit of Genetics and Developmental Biology, Institut Curie, CNRS UMR3215, INSERM U934, Paris, France
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  • A. Hernandez,

    1. Maine Medical Center Research Institute, Scarborough, ME, USA
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  • A. C. Ferguson-Smith

    Corresponding author
    1. Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
    Current affiliation:
    1. Department of Genetics, University of Cambridge, Cambridge, UK
    • Correspondence: A. C. Ferguson-Smith, Department of Physiology, Development and Neuroscience,University of Cambridge, Physiology Building, Downing Street, Cambridge, CB2 3EG, UK

      E-mail: afsmith@mole.bio.cam.ac.uk

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Abstract

Aim

Disruption to insulin-like growth factor (IGF) signalling pathways during early life causes growth retardation and defects of developing metabolic organs that can alter set points of energy homeostasis for a lifetime. Inheritance of two maternal copies of human chromosome 14q32.2 (Temple syndrome) causes severe foetal growth retardation and post-natal failure to thrive. Disruption of imprinted gene dosage in the orthologous region on mouse chromosome 12 also affects growth. Here, we investigated whether altering chromosome 12-imprinted gene dosage can affect IGF signalling.

Methods

We investigated mice with a transgene insertion at the imprinted domain of chromosome 12. This lesion causes misexpression of neighbouring genes such that the expression of non-coding RNAs is elevated, and levels of delta-like homologue 1 (Dlk1), retrotransposon-like 1 (Rtl1) and deiodinase 3 (Dio3) transcripts are reduced.

Results

We observed three key phenotypes in these mice: (i) embryonic growth retardation associated with altered expression of IGF1 binding proteins, (ii) peri-natal failure to thrive accompanied by hypothyroidism and low serum IGF1. Unexpectedly this phenotype was growth hormone independent. (iii) Adult animals had reduced glucose tolerance as a result of endocrine pancreatic insufficiency.

Conclusions

We propose that all of these phenotypes are attributable to impaired IGF action and show for the first time that the chromosome 12 cluster in the mouse is an imprinted locus that modulates the IGF signalling pathway. We propose that growth retardation observed in human Temple syndrome might have a similar cause.

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