title: Deletion of Gtl2, imprinted non-coding RNA, with its differentially methylated region induces lethal parent-origin-dependent defects in mice.
abstract: 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.
authors.affiliation: Department of Bioscience, Tokyo University of Agriculture, Setagaya-ku, Tokyo, Japan.
authors.forename: Nozomi
authors.initials: N
authors.lastname: Takahashi
authors.forename: Akira
authors.initials: A
authors.lastname: Okamoto
authors.forename: Ryota
authors.initials: R
authors.lastname: Kobayashi
authors.forename: Motomu
authors.initials: M
authors.lastname: Shirai
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Obata
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Ogawa
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sotomaru
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kono
mesh_terms: D000818:Animals; D019175:DNA Methylation; D005260:Female; D018392:Genomic Imprinting; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics*; D017384:Sequence Deletion
chemical_list: C422882:MEG3 non-coding RNA, mouse; D011506:Proteins; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated