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:

Distinct physiological and behavioural functions for parental alleles of imprinted Grb10

Nature volume 469, pages 534–538 (2011)Cite this article

Subjects

Abstract

Imprinted genes, defined by their preferential expression of a single parental allele, represent a subset of the mammalian genome and often have key roles in embryonic development1, but also postnatal functions including energy homeostasis2 and behaviour3,4. When the two parental alleles are unequally represented within a social group (when there is sex bias in dispersal and/or variance in reproductive success)5,6, imprinted genes may evolve to modulate social behaviour, although so far no such instance is known. Predominantly expressed from the maternal allele during embryogenesis, Grb10 encodes an intracellular adaptor protein that can interact with several receptor tyrosine kinases and downstream signalling molecules7. Here we demonstrate that within the brain Grb10 is expressed from the paternal allele from fetal life into adulthood and that ablation of this expression engenders increased social dominance specifically among other aspects of social behaviour, a finding supported by the observed increase in allogrooming by paternal Grb10-deficient animals. Grb10 is, therefore, the first example of an imprinted gene that regulates social behaviour. It is also currently alone in exhibiting imprinted expression from each of the parental alleles in a tissue-specific manner, as loss of the peripherally expressed maternal allele leads to significant fetal and placental overgrowth. Thus Grb10 is, so far, a unique imprinted gene, able to influence distinct physiological processes, fetal growth and adult behaviour, owing to actions of the two parental alleles in different tissues.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Generation and characterization of Grb10KO mutants.
Figure 2: Grb10 expression in the mouse brain.
Figure 3: Increased social dominance in Grb10KO +/ p mice.

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. Smith, F. M., Garfield, A. S. & Ward, A. Regulation of growth and metabolism by imprinted genes. Cytogenet. Genome Res. 113, 279–291 (2006)

    Article  CAS  Google Scholar 

  3. Davies, W., Isles, A. R. & Wilkinson, L. S. Imprinted gene expression in the brain. Neurosci. Biobehav. Rev. 29, 421–430 (2005)

    Article  CAS  Google Scholar 

  4. Isles, A. R., Davies, W. & Wilkinson, L. S. Genomic imprinting and the social brain. Phil. Trans. R. Soc. B 361, 2229–2237 (2006)

    Article  CAS  Google Scholar 

  5. Haig, D. Genomic imprinting, sex-biased dispersal, and social behavior. Ann. NY Acad. Sci. 907, 149–163 (2000)

    Article  ADS  CAS  Google Scholar 

  6. Ubeda, F. & Gardner, A. A model for genomic imprinting in the social brain: juveniles. Evolution 64, 2587–2600 (2010)

    Article  Google Scholar 

  7. Holt, L. J. & Siddle, K. Grb10 and Grb14: enigmatic regulators of insulin action—and more? Biochem. J. 388, 393–406 (2005)

    Article  CAS  Google Scholar 

  8. Charalambous, M. et al. Disruption of the imprinted Grb10 gene leads to disproportionate overgrowth by an Igf2-independent mechanism. Proc. Natl Acad. Sci. USA 100, 8292–8297 (2003)

    Article  ADS  CAS  Google Scholar 

  9. Arnaud, P. et al. Conserved methylation imprints in the human and mouse GRB10 genes with divergent allelic expression suggests differential reading of the same mark. Hum. Mol. Genet. 12, 1005–1019 (2003)

    Article  CAS  Google Scholar 

  10. Hikichi, T., Kohda, T., Kaneko-Ishino, T. & Ishino, F. Imprinting regulation of the murine Meg1/Grb10 and human GRB10 genes; roles of brain-specific promoters and mouse-specific CTCF-binding sites. Nucleic Acids Res. 31, 1398–1406 (2003)

    Article  CAS  Google Scholar 

  11. Monk, D. et al. Reciprocal imprinting of human GRB10 in placental trophoblast and brain: evolutionary conservation of reversed allelic expression. Hum. Mol. Genet. 18, 3066–3074 (2009)

    Article  CAS  Google Scholar 

  12. Yamasaki-Ishizaki, Y. et al. Role of DNA methylation and histone H3 lysine 27 methylation in tissue-specific imprinting of mouse Grb10. Mol. Cell. Biol. 27, 732–742 (2007)

    Article  CAS  Google Scholar 

  13. Gregg, C. et al. High-resolution analysis of parent-of-origin allelic expression in the mouse brain. Science 329, 643–648 (2010)

    Article  ADS  CAS  Google Scholar 

  14. Sanz, L. A. et al. A mono-allelic bivalent chromatin domain controls tissue-specific imprinting at Grb10. EMBO J. 27, 2523–2532 (2008)

    Article  CAS  Google Scholar 

  15. Charalambous, M. et al. Maternally-inherited Grb10 reduces placental size and efficiency. Dev. Biol. 337, 1–8 (2010)

    Article  CAS  Google Scholar 

  16. Smith, F. M. et al. Mice with a disruption of the imprinted Grb10 gene exhibit altered body composition, glucose homeostasis, and insulin signaling during postnatal life. Mol. Cell. Biol. 27, 5871–5886 (2007)

    Article  CAS  Google Scholar 

  17. Plagge, A. et al. Imprinted Nesp55 influences behavioral reactivity to novel environments. Mol. Cell. Biol. 25, 3019–3026 (2005)

    Article  CAS  Google Scholar 

  18. Kozlov, S. V. et al. The imprinted gene Magel2 regulates normal circadian output. Nature Genet. 39, 1266–1272 (2007)

    Article  CAS  Google Scholar 

  19. Spencer, C. M. et al. Altered anxiety-related and social behaviors in the Fmr1 knockout mouse model of fragile X syndrome. Genes Brain Behav. 4, 420–430 (2005)

    Article  CAS  Google Scholar 

  20. Sarna, J. R., Dyck, R. H. & Whishaw, I. Q. The Dalila effect: C57BL6 mice barber whiskers by plucking. Behav. Brain Res. 108, 39–45 (2000)

    Article  CAS  Google Scholar 

  21. Keverne, B. Monoallelic gene expression and mammalian evolution. Bioessays 31, 1318–1326 (2009)

    Article  CAS  Google Scholar 

  22. Wolf, J. B. & Hager, R. A maternal–offspring coadaptation theory for the evolution of genomic imprinting. PLoS Biol. 4, 2238–2243 (2006)

    Article  CAS  Google Scholar 

  23. Kaplan, J. R., Manuck, S. B., Fontenot, M. B. & Mann, J. J. Central nervous system monoamine correlates of social dominance in cynomolgus monkeys (Macaca fascicularis). Neuropsychopharmacology 26, 431–443 (2002)

    Article  CAS  Google Scholar 

  24. Raleigh, M. J. et al. Serotonergic mechanisms promote dominance acquisition in adult male vervet monkeys. Brain Res. 559, 181–190 (1991)

    Article  CAS  Google Scholar 

  25. Edwards, C. A. & Ferguson-Smith, A. C. Mechanisms regulating imprinted genes in clusters. Curr. Opin. Cell Biol. 19, 281–289 (2007)

    Article  CAS  Google Scholar 

  26. Blagitko, N. et al. Human GRB10 is imprinted and expressed from the paternal and maternal allele in a highly tissue- and isoform-specific fashion. Hum. Mol. Genet. 9, 1587–1595 (2000)

    Article  CAS  Google Scholar 

  27. Nagy, A., Gertensenstein, K., Vintersten, K. & Behringer, R. Manipulating the Mouse Embryo: A Laboratory Manual 3rd edn (Cold Spring Harbor Laboratory Press, 2003)

    Google Scholar 

  28. Bennett, W. R., Crew, T. E., Slack, J. M. & Ward, A. Structural-proliferative units and organ growth: effects of insulin-like growth factor 2 on the growth of colon and skin. Development 130, 1079–1088 (2003)

    Article  CAS  Google Scholar 

  29. Przydzial, M. J. et al. Nutritional state influences Nociceptin/Orphanin FQ peptide receptor expression in the dorsal raphe nucleus. Behav. Brain Res. 206, 313–317 (2009)

    Article  Google Scholar 

  30. Rousseau, S. J., Jones, I. W., Pullar, I. A. & Wonnacott, S. Presynaptic α7 and non-α7 nicotinic acetylcholine receptors modulate [3H]d-aspartate release from rat frontal cortex in vitro . Neuropharmacology 49, 59–72 (2005)

    Article  CAS  Google Scholar 

  31. Ainscough, J. F. et al. Imprinting of Igf2 and H19 from a 130 kb YAC transgene. Development 124, 3621–3632 (1997)

    CAS  PubMed  Google Scholar 

  32. Morales, M. A. et al. Localization of choline acetyltransferase in rat peripheral sympathetic neurons and its coexistence with nitric oxide synthase and neuropeptides. Proc. Natl Acad. Sci. USA 92, 11819–11823 (1995)

    Article  ADS  CAS  Google Scholar 

  33. Isles, A. R. et al. Urinary odour preferences in mice. Nature 409, 783–784 (2001)

    Article  ADS  CAS  Google Scholar 

  34. Nevison, C. M. et al. The ownership signature in mouse scent marks is involatile. Proc. R. Soc. Lond. B 270, 1957–1963 (2003)

    Article  CAS  Google Scholar 

  35. Doe, C. M. et al. Loss of the imprinted snoRNA mbii-52 leads to increased 5htr2c pre-RNA editing and altered 5HT2CR-mediated behaviour. Hum. Mol. Genet. 18, 2140–2148 (2009)

    Article  CAS  Google Scholar 

  36. Dalley, J. W. et al. Distinct changes in cortical acetylcholine and noradrenaline efflux during contingent and noncontingent performance of a visual attentional task. J. Neurosci. 21, 4908–4914 (2001)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank S. Wonnacott for reagents, the University of Bath Biological Services Unit and S. Routley for technical assistance, I. Jones and P. Mitchell for advice and C. Tickle for comments on the manuscript. We acknowledge funding of the work from the Biotechnology and Biological Sciences Research Council, Medical Research Council, Wellcome Trust and external benefactors.

Author information

Author notes

  1. Alastair S. Garfield

    Present address: Present address: Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK.,

  2. Michael Cowley

    Present address: Present address:Department of Medical and Molecular Genetics, King’s College London, 8th Floor Tower Wing, Guy’s Hospital, London SE1 9RT, UK,

Authors and Affiliations

  1. Department of Biology & Biochemistry and Centre for Regenerative Medicine, University of Bath, Claverton Down, Bath BA2 7AY, UK,

    Alastair S. Garfield, Michael Cowley, Florentia M. Smith, Kim Moorwood, Joanne E. Stewart-Cox, Laurence D. Hurst & Andrew Ward

  2. Behavioural Genetics Group, MRC Centre for Neuropsychiatric Genetics and Genomics, Neuroscience and Mental Health Research Institute, Schools of Medicine and Psychology, Cardiff University, Cardiff CF14 4XN, UK ,

    Alastair S. Garfield, Kerry Gilroy, Sian Baker, Lawrence S. Wilkinson & Anthony R. Isles

  3. Behavioural and Clinical Neuroscience Institute and Department of Experimental Psychology, University of Cambridge, Downing Street, Cambridge CB2 3EB, UK,

    Jing Xia & Jeffrey W. Dalley

  4. Department of Psychiatry, University of Cambridge, Addenbrooke’s Hospital, Hill’s Road, Cambridge CB2 2QQ, UK,

    Jeffrey W. Dalley

Authors
  1. Alastair S. Garfield
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael Cowley
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Florentia M. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kim Moorwood
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Joanne E. Stewart-Cox
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kerry Gilroy
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sian Baker
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jing Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jeffrey W. Dalley
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Laurence D. Hurst
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Lawrence S. Wilkinson
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Anthony R. Isles
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Andrew Ward
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A.W. and A.S.G. conceived the project and interpreted the data, with input from L.D.H., A.R.I. and L.S.W.; K.M. and J.E.S.-C. generated the Grb10KO mice; A.S.G. performed most of the experiments with contributions from M.C., J.W.D., S.B., K.G., A.R.I., F.M.S., J.X. and A.W.; A.S.G. and A.W. jointly wrote the manuscript.

Corresponding author

Correspondence to Andrew Ward.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

The file contains Supplementary Table 1 and Supplementary Figures 1-6 with legends. (PDF 6698 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Garfield, A., Cowley, M., Smith, F. et al. Distinct physiological and behavioural functions for parental alleles of imprinted Grb10. Nature 469, 534–538 (2011). https://doi.org/10.1038/nature09651

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature09651

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

Advanced 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