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:

Role of retrotransposon-derived imprinted gene, Rtl1, in the feto-maternal interface of mouse placenta

Nature Genetics volume 40, pages 243–248 (2008)Cite this article

Abstract

Eutherian placenta, an organ that emerged in the course of mammalian evolution, provides essential architecture, the so-called feto-maternal interface, for fetal development by exchanging nutrition, gas and waste between fetal and maternal blood. Functional defects of the placenta cause several developmental disorders, such as intrauterine growth retardation in humans and mice. A series of new inventions and/or adaptations must have been necessary to form and maintain eutherian chorioallantoic placenta, which consists of capillary endothelial cells and a surrounding trophoblast cell layer(s)1. Although many placental genes have been identified2, it remains unknown how the feto-maternal interface is formed and maintained during development, and how this novel design evolved. Here we demonstrate that retrotransposon-derived Rtl1 (retrotransposon-like 1), also known as Peg11 (paternally expressed 11), is essential for maintenance of the fetal capillaries, and that both its loss and its overproduction cause late-fetal and/or neonatal lethality in mice.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: Pedigree of Rtl1 KO mice.
Figure 2: Histological abnormalities observed in day 15.5 Pat-KO placentas and in day 18.5 Mat-KO placentas.
Figure 3: Placental transfer assay.
Figure 4: Rtl1 protein localization in the placentas at 18.5 d.p.c. by immunohistochemistry.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Rossant, J. & Cross, J.C. Placental development: lessons from mouse mutants. Nat. Rev. Genet. 2, 538–548 (2001).

    Article  CAS  Google Scholar 

  2. Watson, E.D. & Cross, J.C. Development of structures and transport functions in the mouse placenta. Physiology (Bethesda) 20, 180–193 (2005).

    CAS  Google Scholar 

  3. Seitz, H. et al. Imprinted microRNA genes transcribed antisense to a reciprocally imprinted retrotransposon-like gene. Nat. Genet. 34, 261–262 (2003).

    Article  CAS  Google Scholar 

  4. Cattanach, B.M. & Rasverry, C.V. Evidence of imprinting involving the distal region of Chr 12. Mouse Genome 91, 858 (1993).

    Google Scholar 

  5. Georgiades, P., Watkins, M., Surani, M.A. & Ferguson-Smith, A.C. Parental origin-specific developmental defects in mice with uniparental disomy for chromosome 12. Development 127, 4719–4728 (2000).

    CAS  Google Scholar 

  6. Tevendale, M., Watkins, M., Rasberry, C., Cattanach, B. & Ferguson-Smith, A.C. Analysis of mouse conceptuses with uniparental duplication/deficiency for distal chromosome 12: comparison with chromosome 12 uniparental disomy and implications for genomic imprinting. Cytogenet. Genome Res. 113, 215–222 (2006).

    Article  CAS  Google Scholar 

  7. Davis, E. et al. RNAi-mediated allelic trans-interaction at the imprinted Rtl1/Peg11 locus. Curr. Biol. 15, 743–749 (2005).

    Article  CAS  Google Scholar 

  8. Takada, S. et al. Epigenetic analysis of the Dlk1-Gtl2 imprinted domain on mouse chromosome 12: implications for imprinting control from comparison with Igf2-H19. Hum. Mol. Genet. 11, 77–86 (2002).

    Article  CAS  Google Scholar 

  9. Lin, S.P. et al. Asymmetric regulation of imprinting on the maternal and paternal chromosomes at the Dlk1-Gtl2 imprinted cluster on mouse chromosome 12. Nat. Genet. 35, 97–102 (2003).

    Article  CAS  Google Scholar 

  10. Constância, M. et al. Placental-specific IGF-II is a major modulator of placental and fetal growth. Nature 417, 945–948 (2002).

    Article  Google Scholar 

  11. Sibley, C.P. et al. Placental-specific insulin-like growth factor 2 (Igf2) regulates the diffusional exchange characteristics of the mouse placenta. Proc. Natl. Acad. Sci. USA 101, 8204–8208 (2004).

    Article  CAS  Google Scholar 

  12. Angiolini, E. et al. Regulation of placental efficiency for nutrient transport by imprinted genes. Placenta 27 (Suppl. A), S98–S102 (2006).

    Article  Google Scholar 

  13. Moon, Y.S. et al. Mice lacking paternally expressed Pref-1/Dlk1 display growth retardation and accelerated adiposity. Mol. Cell. Biol. 22, 5585–5592 (2002).

    Article  CAS  Google Scholar 

  14. Hernandez, A., Martinez, M.E., Fiering, S., Galton, V.A. & St Germain, D. Type 3 deiodinase is critical for the maturation and function of the thyroid axis. J. Clin. Invest. 116, 476–484 (2006).

    Article  CAS  Google Scholar 

  15. Georgiades, P., Watkins, M., Burton, G.J. & Ferguson-Smith, A.C. Roles for genomic imprinting and the zygotic genome in placental development. Proc. Natl. Acad. Sci. USA 98, 4522–4527 (2001).

    Article  CAS  Google Scholar 

  16. Butler, M., Goodwin, T., Simpson, M., Singh, M. & Poulter, R. Vertebrate LTR retrotransposons of the Tf1/sushi group. J. Mol. Evol. 52, 260–274 (2001).

    Article  CAS  Google Scholar 

  17. Lynch, C. & Tristem, M. A co-opted gypsy-type LTR-retrotransposon is conserved in the genomes of humans, sheep, mice, and rats. Curr. Biol. 13, 1518–1523 (2003).

    Article  CAS  Google Scholar 

  18. Ono, R. et al. Deletion of Peg10, an imprinted gene acquired from a retrotransposon, causes early embryonic lethality. Nat. Genet. 38, 101–106 (2006).

    Article  CAS  Google Scholar 

  19. Brandt, J. et al. Transposable elements as a source of genetic innovation: expression and evolution of a family of retrotransposon-derived neogenes in mammals. Gene 345, 101–111 (2005).

    Article  CAS  Google Scholar 

  20. Youngson, N.A., Kocialkowski, S., Peel, N. & Ferguson-Smith, A.C. A small family of sushi-class retrotransposon-derived genes in mammals and their relation to genomic imprinting. J. Mol. Evol. 61, 481–490 (2005).

    Article  CAS  Google Scholar 

  21. Kagami, M. et al. Deletions and epimutations affecting the human 14q32.2 imprinted region in individuals with paternal and maternal upd(14)-like phenotypes. Nat. Genet. advance online publication, 10.1038/ng.2007.56 (6 January 2008).

  22. Gould, S. & Vrba, S. Exaptation—a missing term in the science of form. Paleobiology 8, 4–15 (1982).

    Article  Google Scholar 

  23. Brosius, J. & Gould, S.J. On “genomenclature”: a comprehensive (and respectful) taxonomy for pseudogenes and other “junk DNA”. Proc. Natl. Acad. Sci. USA 89, 10706–10710 (1992).

    Article  CAS  Google Scholar 

  24. Smit, A.F. Interspersed repeats and other mementos of transposable elements in mammalian genomes. Curr. Opin. Genet. Dev. 9, 657–663 (1999).

    Article  CAS  Google Scholar 

  25. Mi, S. et al. Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis. Nature 403, 785–789 (2000).

    Article  CAS  Google Scholar 

  26. Kazazian, H.H., Jr. Mobile elements: drivers of genome evolution. Science 303, 1626–1632 (2004).

    Article  CAS  Google Scholar 

  27. Dupressoir, A. et al. Syncytin-A and syncytin-B, two fusogenic placenta-specific murine envelope genes of retroviral origin conserved in Muridae. Proc. Natl. Acad. Sci. USA 102, 725–730 (2005).

    Article  CAS  Google Scholar 

  28. Bejerano, G. et al. A distal enhancer and an ultraconserved exon are derived from a novel retroposon. Nature 441, 87–90 (2006).

    Article  CAS  Google Scholar 

  29. Biémont, C. & Vieira, C. Genetics: junk DNA as an evolutionary force. Nature 443, 521–524 (2006).

    Article  Google Scholar 

  30. Sekita, Y. et al. Aberrant regulation of imprinted gene expression in Gtl2lacZ mice. Cytogenet. Genome Res. 113, 223–229 (2006).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank S. Aizawa of Center for Developmental Biology, RIKEN for providing the DT-A vector that was used for making Rtl1 KO construct, E. Robertson of University of Oxford for the CCE ES cells, M. Constancia of University of Cambridge for placenta functional assay protocol, Y. Nakahara and M. Takabe of the Mitsubishi Kagaku Institute of Life Sciences for animal breeding and H. Hasegawa, N. Kawabe and A. Akatsuka of the Tokai University and S. Ichinose of the Tokyo Medical and Dental University for their assistance in immunohistochemistry and electron microscopy along with helpful discussion. This work was supported by grants from Creative Science Research, the research program of Japan Society for the Promotion of Science (JSPS), the Uehara Memorial Science Foundation, the Mitsubishi Foundation and the Ministry of Health, Labour and Welfare for Child Health and Development (17C-2) and a Grant-in-Aid for Scientific Research on Priority Areas form the Ministry of Education, Culture, Sports, Science and Technology of Japan (1508023) to F.I., the grant for young investigators from Medical Research Institute to Y.S., and the Asahi Glass Foundation and JSPS, Grants-in Aid for Scientific Research to T.K.-I. Pacific Edit reviewed the manuscript before submission.

Author information

Author notes

  1. Minesuke Yokoyama

    Present address: Present address: Brain Research Institute, Niigata University, 1-757 Asahimachi-dori, Niigata 951-8585, Japan.,

Authors and Affiliations

  1. Department of Epigenetics, Medical Research Institute, Tokyo Medical and Dental University, 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo, 101-0062, Japan

    Yoichi Sekita, Ryuichi Ono, Noriko Wakisaka, Takashi Kohda & Fumitoshi Ishino

  2. Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama, 226-8501, Japan

    Hirotaka Wagatsuma

  3. Mitsubishi Kagaku Institute of Life Sciences, 11 Minamiooya, Machida, Tokyo, 194-8511, Japan

    Kenji Nakamura, Toshiaki Hino, Rika Suzuki-Migishima & Minesuke Yokoyama

  4. Department of Endocrinology and Metabolism, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan

    Masayo Kagami & Tsutomu Ogata

  5. School of Health Sciences, Tokai University, Bohseidai, Isehara, Kanagawa, 259-1193, Japan

    Noriko Wakisaka & Tomoko Kaneko-Ishino

  6. BioResource Center, RIKEN, 3-1-1 Koyadai, Tsukuba, Ibaraki, 305-0074, Japan

    Atsuo Ogura

Authors
  1. Yoichi Sekita
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hirotaka Wagatsuma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kenji Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ryuichi Ono
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Masayo Kagami
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Noriko Wakisaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Toshiaki Hino
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Rika Suzuki-Migishima
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Takashi Kohda
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Atsuo Ogura
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Tsutomu Ogata
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Minesuke Yokoyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Tomoko Kaneko-Ishino
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Fumitoshi Ishino
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Most analyses in this work were performed by Y.S. with collaboration of H.W., R.O., N.W., T.K. and M.K. in molecular and histological experiments. Construction of Rtl1 targeting vector was done by H.W. under supervision of K.N. and M.Y., and KO mice were produced by T.H., R.S.-M., K.N. and M.Y. The study was designed and coordinated by T.K.-I. and F.I., and the results were discussed by A.O., T.O., T.K.-I. and F.I. The paper was written by Y.S. and F.I.

Corresponding authors

Correspondence to Tomoko Kaneko-Ishino or Fumitoshi Ishino.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5, Supplementary Tables 1–3 (PDF 1297 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sekita, Y., Wagatsuma, H., Nakamura, K. et al. Role of retrotransposon-derived imprinted gene, Rtl1, in the feto-maternal interface of mouse placenta. Nat Genet 40, 243–248 (2008). https://doi.org/10.1038/ng.2007.51

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.2007.51

This article is cited by

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