Overexpression of Polycomb-group gene rae28 in cardiomyocytes does not complement abnormal cardiac morphogenesis in mice lacking rae28 but causes dilated cardiomyopathy.
The Polycomb-group genes (PcG) are widely conserved from Drosophila to mammals and are required for maintaining positional information during development. The rae28 gene (rae28) is a member of the mouse PcG. Mice deficient in rae28 (rae28(-/-)) demonstrated that rae28 has a role not only in anteroposterior patterning but also in cardiac morphogenesis. In this study we generated transgenic mice with ubiquitous or cardiomyocyte-specific exogenous rae28 expression. Genetic complementation experiments with these transgenic mice showed that ubiquitous expression of rae28 could reverse the cardiac anomalies in rae28(-/-), whereas cardiomyocyte-specific expression of rae28 could not, suggesting that rae28 is involved in cardiac morphogenesis through a noncardiomyocyte pathway. Interestingly, however, cardiomyocyte-specific overexpression of rae28 caused dilated cardiomyopathy, which was associated with cardiomyocyte apoptosis, abnormal myofibrils, and severe heart failure. Cardiac expression of rae28 was predominant in the early embryonic stage, whereas that of the other PcG members was relatively constitutive. Because rae28 forms multimeric complexes with other PcG proteins in the nucleus, it is presumed that constitutive cardiomyocyte-specific rae28 overexpression impaired authentic PcG functions in the heart. rae28-induced dilated cardiomyopathy may thus provide a clue for clarifying the direct role of PcG in the maintenance of cardiomyocytes.
Koga
Hideyuki
H
Department of Developmental Biology and Medicine, Osaka Medical Center for Cancer and Cardiovascular Diseases, Higashinari, Osaka, Japan.
Kaji
Yoshikazu
Y
Nishii
Kiyomasa
K
Shirai
Manabu
M
Tomotsune
Daihachiro
D
Osugi
Tomoaki
T
Sawada
Akihisa
A
Kim
Ji Yoo
JY
Hara
Junichi
J
Miwa
Takeshi
T
Yamauchi-Takihara
Keiko
K
Shibata
Yosaburo
Y
Takihara
Yoshihiro
Y
D000818:Animals; D001358:Avian Sarcoma Viruses / Q000235:genetics; D015152:Blotting, Northern; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins; D004195:Disease Models, Animal; D004452:Echocardiography; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D007178:Inbreeding; D008136:Longevity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000096:biosynthesis / Q000235:genetics; D063150:Polycomb Repressive Complex 1; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D024723:Ventricular Myosins / Q000235:genetics
D002352:Carrier Proteins; D018398:Homeodomain Proteins; C103827:Phc1 protein, mouse; D012333:RNA, Messenger; D063150:Polycomb Repressive Complex 1; D024723:Ventricular Myosins; D018995:Myosin Heavy Chains