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First published online 17 September 2009
doi: 10.1242/dev.036061

Development 136, 3413-3421 (2009)
Published by The Company of Biologists 2009
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H19 acts as a trans regulator of the imprinted gene network controlling growth in mice

Anne Gabory1, Marie-Anne Ripoche1, Anne Le Digarcher2, Françoise Watrin3, Ahmed Ziyyat1, Thierry Forné4, Hélène Jammes5, Justin F. X. Ainscough6, M. Azim Surani7, Laurent Journot2 and Luisa Dandolo1,*

1 Genetics and Development Department, Inserm U567, CNRS UMR 8104, University of Paris Descartes, Institut Cochin, Paris, France.
2 Institut de Genomique Fonctionnelle, CNRS UMR 5203, INSERM U661, University of Montpellier II, Montpellier, France.
3 Inserm U901-INMED, Parc scientifique de Luminy, Marseille, France.
4 Institut de Génétique Moléculaire de Montpellier, CNRS UMR 5535, University of Montpellier II, Montpellier, France.
5 PHASE Department, INRA, Jouy en Josas, France.
6 Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds LS2 9JT, UK.
7 Wellcome Trust/Cancer Research UK Gurdon Institute of Cancer and Developmental Biology, University of Cambridge, Cambridge CB2 1QN, UK.

* Author for correspondence (luisa.dandolo{at}inserm.fr)

Accepted 11 August 2009

The imprinted H19 gene produces a non-coding RNA of unknown function. Mice lacking H19 show an overgrowth phenotype, due to a cis effect of the H19 locus on the adjacent Igf2 gene. To explore the function of the RNA itself, we produced transgenic mice overexpressing H19. We observed postnatal growth reduction in two independent transgenic lines and detected a decrease of Igf2 expression in embryos. An extensive analysis of several other genes from the newly described imprinted gene network (IGN) was performed in both loss- and gain-of-function animals. We found that H19 deletion leads to the upregulation of several genes of the IGN. This overexpression is restored to the wild-type level by transgenic expression of H19. We therefore propose that the H19 gene participates as a trans regulator in the fine-tuning of this IGN in the mouse embryo. This is the first in vivo evidence of a functional role for the H19 RNA. Our results also bring further experimental evidence for the existence of the IGN and open new perspectives in the comprehension of the role of genomic imprinting in embryonic growth and in human imprinting pathologies.

Key words: H19, Igf2, Transgenic mouse models, Imprinted gene network (IGN), Genomic imprinting, Non-coding RNA


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Development 2009 136: e2002. [Full Text]  





© The Company of Biologists Ltd 2009