Energy deprivation and a deficiency in downstream metabolic target genes during the onset of embryonic heart failure in RXRalpha-/- embryos.
RXRalpha null mutant mice display ocular and cardiac malformations, liver developmental delay, and die from cardiac failure around embryonic day (E) 14.5 pc. To dissect the molecular basis of the RXRalpha-associated cardiomyopathy, we performed subtractive hybridization and systematically characterized putative downstream target genes that were selectively lacking in the mutant embryos, both at early (E10.5) and late (E13.5) stages of mouse embryonic development. Approximately 50% of the subtracted clones (61/115) encoded proteins involved in intermediary metabolism and electron transport, suggesting an energy deficiency in the RXRalpha-/- embryos. In particular, clone G1, which encodes subunit 14.5b of the NADH-ubiquinone dehydrogenase complex, displayed a dose-dependent expression in the wild-type, heterozygous and RXRalpha mutant mice. This gene was also downregulated in a retinoid-deficient rat embryo model. ATP content and medium Acyl-CoA dehydrogenase mRNA were lower in RXRalpha mutant hearts compared to wild-type mice. Ultrastructural studies showed that the density of mitochondria per myocyte was higher in the RXRalpha mutant compared to wild-type littermates. We propose a model whereby defects in intermediary metabolism may be a causative factor of the RXRalpha-/- phenotype and resembles an embryonic form of dilated cardiomyopathy.
Ruiz-Lozano
P
P
Department of Medicine and Center for Molecular Genetics, University of California, San Diego, La Jolla 92093, USA.
Smith
S M
SM
Perkins
G
G
Kubalak
S W
SW
Boss
G R
GR
Sucov
H M
HM
Evans
R M
RM
Chien
K R
KR
D042964:Acyl-CoA Dehydrogenase; D044944:Acyl-CoA Dehydrogenases / Q000235:genetics; D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000196:embryology* / Q000235:genetics; D003001:Cloning, Molecular / Q000379:methods; D018076:DNA, Complementary / Q000235:genetics; D042967:Electron Transport Complex I; D004734:Energy Metabolism / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D015723:Gene Library; D005796:Genes / Q000235:genetics / Q000502:physiology*; D006321:Heart / Q000196:embryology*; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart; D009206:Myocardium / Q000737:chemistry / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011922:Rats, Mutant Strains; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000502:physiology*; D047488:Retinoid X Receptors; D012176:Retinoids; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D018076:DNA, Complementary; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D012176:Retinoids; D014157:Transcription Factors; D000255:Adenosine Triphosphate; D044944:Acyl-CoA Dehydrogenases; D042964:Acyl-CoA Dehydrogenase; D009247:NADH, NADPH Oxidoreductases; D042967:Electron Transport Complex I