The Polycomb-group gene Rae28 sustains Nkx2.5/Csx expression and is essential for cardiac morphogenesis.
The Polycomb-group (PcG) gene Rae28 is a mammalian homologue of the Drosophila gene polyhomeotic. PcG genes are known to maintain transcription states, once initiated, probably by regulating chromatin structure. Since homozygous Rae28-deficient (Rae28(-/-)) mice displayed cardiac anomalies similar to congenital heart diseases in humans, we examined the role of Rae28 in cardiac morphogenesis at the molecular level. In Rae28(-/-) embryos, expression of the cardiac selector gene Nkx2.5/Csx (Nkx2.5) was initiated properly but was not sufficiently sustained later in development. This impaired expression of Nkx2.5 in the maintenance phase proved to have a crucial effect on cardiac morphogenesis, as demonstrated by the results of a genetic complementation experiment in which the cardiac anomalies were suppressed by overexpression of human NKX2.5/CSX1 in Rae28(-/-) embryos. Ubiquitous expression of exogenous Rae28 likewise restored the impaired Nkx2.5 expression in Rae28(-/-) embryos, further supporting the notion that Rae28 sustains Nkx2.5 expression in cardiomyocytes. Thus, our data show that a mammalian PcG gene can play a key role in organogenesis by helping to maintain the expression of a selector gene.
Department of Developmental Biology and Medicine, Osaka Medical Center for Cancer and Cardiovascular Diseases, Higashinari, Japan.
Manabu
M
Shirai
Tomoaki
T
Osugi
Hideyuki
H
Koga
Yoshikazu
Y
Kaji
Eiki
E
Takimoto
Issei
I
Komuro
Junichi
J
Hara
Takeshi
T
Miwa
Keiko
K
Yamauchi-Takihara
Yoshihiro
Y
Takihara
D000818:Animals; D002352:Carrier Proteins; D005318:Fetal Heart / Q000196:embryology*; D018507:Gene Expression Regulation, Developmental; D005801:Genes, Homeobox; D005816:Genetic Complementation Test; D006330:Heart Defects, Congenital / Q000196:embryology / Q000235:genetics; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics* / Q000502:physiology; D006801:Humans; D017403:In Situ Hybridization; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D063150:Polycomb Repressive Complex 1; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology; D029867:Xenopus Proteins
D002352:Carrier Proteins; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C095552:NKX2-5 protein, human; C484469:Nkx2-5 protein, mouse; C491239:PHC1 protein, human; C103827:Phc1 protein, mouse; D014157:Transcription Factors; D029867:Xenopus Proteins; D063150:Polycomb Repressive Complex 1