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Human Molecular Genetics Advance Access published online on March 4, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp108
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Deletion of Gtl2, imprinted non-coding RNA, with its differentially methylated region induces lethal parent-origin-dependent defects in mice

Nozomi Takahashi1, Okamoto Akira1, Ryota Kobayashi1, Motomu Shirai1, Yayoi Obata1, Hidehiko Ogawa1, Yusuke Sotomaru2 and Tomohiro Kono1,*

1 Department of Bioscience, Tokyo University of Agriculture, Setagaya-ku, Tokyo 156-8502, Japan 2 Natural Science Center for Basic Research and Development, Hiroshima University, Minami-ku, Hiroshima 734-8553, Japan

* To whom correspondence should be addressed. Tel/Fax: +81 354772543; E-mail: tomohiro{at}nodai.ac.jp

Received December 24, 2008; Revised February 16, 2009; Accepted March 3, 2009

The cluster of imprinted genes located in the Dlk1-Dio3 domain spanning 1 Mb plays an essential role in controlling pre- and postnatal growth and differentiation in mice and humans. The failure of parent-of-origin-dependent gene expression in this domain results in grave disorders, leading to death in some cases. However, little is known about the role of maternally expressed non-coding RNAs (ncRNAs) including many miRNAs and snoRNAs in this domain. In order to further understand the role of these ncRNAs, we created Gtl2-mutant mice harboring a 10-kb deletion in exons 1–5. The mutant mice exhibited a very unique inheritance mode: when the deletion was inherited from the mother (Mat-KO), the pups were born with normal phenotypes; however, all of them died within 4 weeks after birth, probably due to severely hypoplastic pulmonary alveoli and hepatocellular necrosis. Mice carrying the paternal deletion (Pat-KO) showed severe growth retardation and perinatal lethality. Interestingly, the homozygous mutants (Homo-KO) survived and developed into fertile adults. Our results show that these phenotypes occur due to altered expression of the Dlk1-Dio3 cluster genes including miRNAs and snoRNAs via the cis and trans effects.


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