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


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.

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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.

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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.

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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.

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Correspondence to Tomoko Kaneko-Ishino or Fumitoshi Ishino.

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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).

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