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RXR alpha mutant mice establish a genetic basis for vitamin A signaling in heart morphogenesis
H M Sucov1, E Dyson, C L Gumeringer
1Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California 92138.
Abstract:
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.
Insights
Retinoic acid receptor (RXR) alpha is essential for embryonic development. Loss of RXR alpha function in mice causes severe heart defects and embryonic lethality, highlighting its role in cardiac morphogenesis.
Area of Science:
- Developmental Biology
- Genetics
- Molecular Biology
Background:
- Retinoic acid signaling is crucial for embryonic development.
- The precise role of Retinoic X Receptor (RXR) alpha in cardiac morphogenesis is not fully understood.
Purpose of the Study:
- To investigate the function of RXR alpha in embryonic development.
- To determine the role of RXR alpha in cardiac morphogenesis and its relation to vitamin A signaling.
Main Methods:
- Generation of a targeted loss-of-function mutation in the mouse RXR alpha gene.
- Analysis of embryonic development and cardiac morphology in homozygous RXR alpha mutant mice.
Main Results:
- Homozygous RXR alpha mutant mice exhibit embryonic lethality between E13.5 and E16.5.
- The primary defect is hypoplastic ventricular development with thinned walls and septation defects.
- The cardiac phenotype mimics aspects of embryonic vitamin A deficiency, implicating RXR alpha in this pathway.
- Cardiac outflow tracts and hepatic differentiation are largely unaffected, suggesting specific roles for RXR alpha.
Conclusions:
- RXR alpha is essential for normal embryonic development, particularly cardiac morphogenesis.
- This study provides the first genetic evidence for RXR alpha's requirement in a hormone response pathway.
- Ventricular chamber development is genetically distinct from outflow tract development in relation to vitamin A signaling.