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The imprinted signaling protein XLαs is required for postnatal adaptation to feeding

Nature Genetics volume 36, pages 818–826 (2004)Cite this article

Abstract

Genomic imprinting, by which maternal and paternal alleles of some genes have different levels of activity, has profound effects on growth and development of the mammalian fetus. The action of imprinted genes after birth, in particular while the infant is dependent on maternal provision of nutrients, is far less well understood. We disrupted a paternally expressed transcript at the Gnas locus, Gnasxl, which encodes the unusual Gsα isoform XLαs. Mice with mutations in Gnasxl have poor postnatal growth and survival and a spectrum of phenotypic effects that indicate that XLαs controls a number of key postnatal physiological adaptations, including suckling, blood glucose and energy homeostasis. Increased cAMP levels in brown adipose tissue of Gnasxl mutants and phenotypic comparison with Gnas mutants suggest that XLαs can antagonize Gsα-dependent signaling pathways. The opposing effects of maternally and paternally expressed products of the Gnas locus provide tangible molecular support for the parental-conflict hypothesis of imprinting.

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Figure 1: The imprinted mouse Gnas locus.
Figure 2: Generation of Gnasxl-deficient mice.
Figure 3: Growth and survival.
Figure 4: Food intake and plasma parameters of energy homeostasis.
Figure 5: Adipose tissue phenotype.
Figure 6: cAMP signaling in adipose tissues.
Figure 7: Postnatal expression pattern of Gnasxl.

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Acknowledgements

We thank W. Reik, P. Hawkins and A. Vidal-Puig for their support and comments on the manuscript; E. Walters for statistical analysis of the data; T. Storck and K. Thomas for providing precursor plasmids for pRAY-Cre; A. Voss for the ES cell line MPI-VI; and the staff at Babraham animal facilities for dedicated husbandry. This work was supported by an Medical Research Council senior fellowship to G.K. and by the Biotechnology and Biological Sciences Research Council.

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Authors and Affiliations

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

    Antonius Plagge, Emma Gordon, Wendy Dean & Gavin Kelsey

  2. Faculty of Medicine, Multi-tech University of Marche, via Tronto 10/a, Ancona, 60020, Italy

    Romina Boiani & Saverio Cinti

  3. MRC Mammalian Genetics Unit, Harwell, Oxfordshire, OX11 0RD, UK

    Jo Peters

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Correspondence to Gavin Kelsey.

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Supplementary information

Supplementary Fig. 1

The Gnasxl mutation does not alter the methylation state of the Gnasxl and Nesp DMRs in cis. (PDF 110 kb)

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Plagge, A., Gordon, E., Dean, W. et al. The imprinted signaling protein XLαs is required for postnatal adaptation to feeding. Nat Genet 36, 818–826 (2004). https://doi.org/10.1038/ng1397

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