Deficiency and overexpression of Rtl1 in the mouse cause distinct muscle abnormalities related to Temple and Kagami-Ogata syndromes.

Moe Kitazawa,Tomoko Kaneko-Ishino,Michihiro Imamura,Fumitoshi Ishino,Shin'Ichi Takeda,Shinichiro Hayashi,Yumiko Oishi,John Wallingford,Sally Dunwoodie

doi:10.1242/dev.185918

Abstract

ABSTRACTTemple and Kagami-Ogata syndromes are genomic imprinting diseases caused by maternal and paternal duplication of human chromosome 14, respectively. They exhibit different postnatal muscle-related symptoms as well as prenatal placental problems. Using the mouse models for these syndromes, it has been demonstrated that retrotransposon gag like 1 [Rtl1, also known as paternally expressed 11 (Peg11)] located in the mouse orthologous imprinted region is responsible for the prenatal placental problems because it is an essential placental gene for maintenance of fetal capillary network during gestation. However, the causative imprinted gene for the postnatal muscle-related symptoms remains unknown. Here, we demonstrate that Rtl1 also plays an important role in fetal/neonatal skeletal muscle development: its deletion and overproduction in mice lead to neonatal lethality associated with severe but distinct skeletal muscle defects, similar to those of Temple and Kagami-Ogata syndromes, respectively. Thus, it is strongly suggested that RTL1 is the major gene responsible for the muscle defects in addition to the placental defects in these two genomic imprinting diseases. This is the first example of an LTR retrotransposon-derived gene specific to eutherians contributing to eutherian skeletal muscle development.

Highlights

Temple and Kagami-Ogata syndromes are caused by maternal and paternal disomy of chromosome 14 [Upd(14)mat and upd(14)pat], respectively
We have previously demonstrated that mouse Rtl1 is one of the major genes responsible for the placental abnormalities characteristic of these two syndromes, and that the severity of the phenotypes of Kagami-Ogata syndrome, such as a bell-shaped thorax and neonatal lethality associated with respiratory problems, is associated with the degree of overproduction of human Retrotransposon gag like 1 (RTL1) (Kagami et al, 2008)
Its expression was detected by at least embryonic day 12.5 (E12.5), while in the skeletal muscles it was detected in E16.5 and E18.5 fetuses and neonates [ postnatal day 0 (P0)]; its expression was gradually reduced after birth and almost entirely disappeared by P15 (Fig. 1A, Figs S3 and S4)

Summary

Introduction

Temple and Kagami-Ogata syndromes are caused by maternal and paternal disomy of chromosome 14 [Upd(14)mat and upd(14)pat], respectively. We have previously demonstrated that mouse Rtl is one of the major genes responsible for the placental abnormalities characteristic of these two syndromes, and that the severity of the phenotypes of Kagami-Ogata syndrome, such as a bell-shaped thorax and neonatal lethality associated with respiratory problems, is associated with the degree of overproduction of human RTL1 (Kagami et al, 2008). Beyond the essential involvement of Rtl in maintaining placental fetal capillaries, the role of Rtl in the respiratory failure and other muscular problems observed in neonates remains unknown, recent studies report that the ectopic expression of ovine RTL1 leads to muscle hypertrophy in mice, which mimics the sheep callipyge phenotype (Charlier et al, 2001; Fleming-Waddell et al, 2009; Byrne et al, 2010; Xu et al, 2015; Mikovic et al, 2018)

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