RXR alpha mutant mice establish a genetic basis for vitamin A signaling in heart morphogenesis.
نویسندگان
چکیده
We have established a targeted loss-of-function mutation in the RXR alpha gene in the mouse germ line that results in embryonic lethality between E13.5 and E16.5 when bred to homozygosity. The major defect responsible for lethality is hypoplastic development of the ventricular chambers of the heart, which is manifest as a grossly thinned ventricular wall with concurrent defects in ventricular septation. This phenotype is identical to a subset of the effects of embryonic vitamin A deficiency and, therefore, establishes RXR alpha as a genetic component of the vitamin A signaling pathway in cardiac morphogenesis. The cardiac outflow tracts and associated vessels, which are populated by derivatives of the neural crest and which are also sensitive to vitamin A deficiency, are normal in homozygous embryos, indicating the genetic independence of ventricular chamber development. Hepatic differentiation was dramatically but transiently retarded yet is histologically and morphologically normal. These results ascribe an essential function for the RXR alpha gene in embryonic development and provide the first evidence of a requirement for RXR in one of its predicted hormone response pathways.
منابع مشابه
RXR alpha deficiency confers genetic susceptibility for aortic sac, conotruncal, atrioventricular cushion, and ventricular muscle defects in mice.
Retinoid-dependent pathways play a central role in regulating cardiac morphogenesis. Recently, we characterized gene-targeted RXR alpha -/- embryos, which display an atrial-like ventricular phenotype with the development of heart failure and lethality at embryonic day 14.5. To quantitate the frequency and complexity of cardiac morphogenic defects, we now use microdissection and scanning electro...
متن کاملSeparation of retinoid X receptor homo- and heterodimerization functions.
As a promiscuous dimerization partner the retinoid X receptor (RXR) can contribute to signaling by multiple nuclear receptors. However, the impact of RXR cosignaling and the possible existence of an RXR homodimer signaling pathway are largely unexplored. We report here on the separation of RXR homo- and heterodimerization as an essential step towards the elucidation of the roles of RXR homo- an...
متن کاملDimerization with retinoid X receptors promotes nuclear localization and subnuclear targeting of vitamin D receptors.
The vitamin D receptor (VDR) acts as heterodimer with the retinoid X receptor alpha (RXR) to control transcriptional activity of target genes. To explore the influence of heterodimerization on the subcellular distribution of these receptors in living cells, we developed a series of fluorescent-protein chimeras. The steady-state distribution of the yellow fluorescent protein-RXR was more nuclear...
متن کاملA transcriptionally silent RXRalpha supports early embryonic morphogenesis and heart development.
Retinoic acid (RA) receptors (RARs) alpha, beta, and gamma heterodimerized with rexinoid receptors (RXRs) alpha, beta, and gamma mediate the RA signal. To analyze the contribution of the transcriptional activity of RXRalpha, the main RXR during embryogenesis, we have engineered a mouse line harboring a transcriptionally silent RXRalpha mutant that lacks the activation functions AF1 and AF2. All...
متن کاملVentricular muscle-restricted targeting of the RXRalpha gene reveals a non-cell-autonomous requirement in cardiac chamber morphogenesis.
Mouse embryos lacking the retinoic acid receptor gene RXR(alpha) die in midgestation from hypoplastic development of the myocardium of the ventricular chambers and consequent cardiac failure. In this study, we address the issue of whether the RXRalpha gene is required in the cardiomyocyte lineage by generating mice that harbor a ventricular restricted deficiency in RXRalpha at the earliest stag...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- Genes & development
دوره 8 9 شماره
صفحات -
تاریخ انتشار 1994