TY - JOUR
T1 - Female mice lacking Ftx lncRNA exhibit impaired X-chromosome inactivation and a microphthalmia-like phenotype
AU - Hosoi, Yusuke
AU - Soma, Miki
AU - Shiura, Hirosuke
AU - Sado, Takashi
AU - Hasuwa, Hidetoshi
AU - Abe, Kuniya
AU - Kohda, Takashi
AU - Ishino, Fumitoshi
AU - Kobayashi, Shin
N1 - Funding Information:
We thank Dr M. Sugimoto at RIKEN BioResource Center for providing the pXist 1986-9498 plasmid, Y. Esaki and S. Nishioka for technical assistance in generating miRNA374/ 421 doubly deficient mouse lines, and A. Hirano for the maintenance of animals. We also thank Drs K. Ohno and Y. Kuroda at Tokyo Medical and Dental University for discussion on human diseases, and Drs S. Nakagawa, M. Okabe and D. Endo for critical reading and discussion. This work was supported by the Japan Science and Technology Agency, Precursory Research for Embryonic Science and Technology (PRESTO) and by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology [23500492, 15H01468, 26430087, 17H05597, 17K07498, and 18H04892] to S.K. The funding bodies had no roles in the study design, data collection and analysis, decision to publish or preparation of the manuscript.
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - X-chromosome inactivation (XCI) is an essential epigenetic process in female mammalian development. Although cell-based studies suggest the potential importance of the Ftx long non-protein-coding RNA (lncRNA) in XCI, its physiological roles in vivo remain unclear. Here we show that targeted deletion of X-linked mouse Ftx lncRNA causes eye abnormalities resembling human microphthalmia in a subset of females but rarely in males. This inheritance pattern cannot be explained by X-linked dominant or recessive inheritance, where males typically show a more severe phenotype than females. In Ftx-deficient mice, some X-linked genes remain active on the inactive X, suggesting that defects in random XCI in somatic cells cause a substantially female-specific phenotype. The expression level of Xist, a master regulator of XCI, is diminished in females homozygous or heterozygous for Ftx deficiency. We propose that loss-of-Ftx lncRNA abolishes gene silencing on the inactive X chromosome, leading to a female microphthalmia-like phenotype.
AB - X-chromosome inactivation (XCI) is an essential epigenetic process in female mammalian development. Although cell-based studies suggest the potential importance of the Ftx long non-protein-coding RNA (lncRNA) in XCI, its physiological roles in vivo remain unclear. Here we show that targeted deletion of X-linked mouse Ftx lncRNA causes eye abnormalities resembling human microphthalmia in a subset of females but rarely in males. This inheritance pattern cannot be explained by X-linked dominant or recessive inheritance, where males typically show a more severe phenotype than females. In Ftx-deficient mice, some X-linked genes remain active on the inactive X, suggesting that defects in random XCI in somatic cells cause a substantially female-specific phenotype. The expression level of Xist, a master regulator of XCI, is diminished in females homozygous or heterozygous for Ftx deficiency. We propose that loss-of-Ftx lncRNA abolishes gene silencing on the inactive X chromosome, leading to a female microphthalmia-like phenotype.
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U2 - 10.1038/s41467-018-06327-6
DO - 10.1038/s41467-018-06327-6
M3 - Article
C2 - 30237402
AN - SCOPUS:85053658206
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3829
ER -