RXRalpha overexpression in cardiomyocytes causes dilated cardiomyopathy but fails to rescue myocardial hypoplasia in RXRalpha-null fetuses.
Retinoid X receptor alpha-null (RXRalpha-null) mutants exhibit hypoplasia of their ventricular myocardium and die at the fetal stage. In the present study, we wished to determine whether transgenic re-expression of RXRalpha in mutant cardiac myocytes could rescue these defects. Two transgenic mouse lines specifically overexpressing an RXRalpha protein in cardiomyocytes were generated, using the cardiac alpha-myosin heavy chain (alpha-MHC) promoter. Breeding the high copy number transgenic line onto an RXRalpha-null genetic background did not prevent the myocardial hypoplasia and fetal lethality associated with the RXRalpha(-/-) genotype, even though the transgene was expressed in the ventricles as early as 10. 5 days post-coitum. These data suggest that the RXRalpha function involved in myocardial growth may correspond to a non-cell-autonomous requirement forsignal orchestrating the growth and differentiation of myocytes. Interestingly, the adult transgenic mice developed a dilated cardiomyopathy, associated with myofibrillar abnormalities and specific deficiencies in respiratory chain complexes I and II, thus providing an additional model for this genetically complex disease.
Subbarayan
V
V
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS-INSERM-ULP-Collège de France, BP 163, 67404 Illkirch Cedex, France.
Mark
M
M
Messadeq
N
N
Rustin
P
P
Chambon
P
P
Kastner
P
P
D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics* / Q000503:physiopathology; D004268:DNA-Binding Proteins / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis / Q000235:genetics*; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*
D004268:DNA-Binding Proteins; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors