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First published online October 9, 2009
doi: 10.1242/10.1242/dev.041061

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The miR-124-Sox9 paramutation: RNA-mediated epigenetic control of embryonic and adult growth

Valérie Grandjean^1,2, Pierre Gounon^3,*, Nicole Wagner^4,5,*, Luc Martin^1,2, Kay D. Wagner^4,5, Florence Bernex⁶, François Cuzin^1,2 and Minoo Rassoulzadegan^1,2,

¹ Inserm U636, F-06108 Nice, France.
² Université de Nice-Sophia Antipolis, Laboratoire de Génétique du Développement Normal et Pathologique, F-06108 Nice, France.
³ Centre Commun de Microscopie Appliquée, Université de Nice-Sophia Antipolis, F-06108 Nice, France.
⁴ Inserm-Avenir U907, F-06107 Nice, France.
⁵ Faculté de Médecine, Université de Nice-Sophia Antipolis, F-06107 Nice, France.
⁶ Institut National de la Recherche Agronomique, Ecole Nationale Vétérinaire d'Alfort, F-94704 Maisons-Alfort, France.

Author for correspondence (minoo{at}unice.fr)

Accepted 2 September 2009

The size of the mammalian body is determined by genetic and environmental factors differentially modulating pre- and postnatal growth. We now report a control of growth acting in the mouse from the first cleavages to the postnatal stages. It was evidenced by a hereditary epigenetic modification (paramutation) created by injection of a miR-124 microRNA into fertilized eggs. From the blastocyst to the adult, mouse pups born after microinjection of this miRNA showed a 30% increase in size. At the blastocyst stage, frequent duplication of the inner cell mass resulted in twin pregnancies. A role of sperm RNA as a transgenerational signal was confirmed by the giant phenotype of the progeny of transgenic males expressing miR-124 during spermiogenesis. In E2.5 to E8.5 embryos, increased levels of several transcripts with sequence homology to the microRNA were noted, including those of Sox9, a gene known for its crucial role in the progenitors of several adult tissues. A role in embryonic growth was confirmed by the large size of embryos expressing a Sox9 DNA transgene. Increased expression in the paramutants was not related to a change in miR-124 expression, but to the establishment of a distinct, heritable chromatin structure in the promoter region of Sox9. While the heritability of body size is not readily accounted for by Mendelian genetics, our results suggest the alternate model of RNA-mediated heritable epigenetic modifications.

Key words: One-cell embryo, Blastocyst, Sox genes, Twins, Non-Mendelian inheritance, Mouse

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				V. Grandjean, P. Gounon, N. Wagner, L. Martin, K. D. Wagner, F. Bernex, F. Cuzin, and M. Rassoulzadegan The miR-124-Sox9 paramutation: RNA-mediated epigenetic control of embryonic and adult growth J. Cell Sci., November 1, 2009; 122(21): e2 - e2. [Full Text]