Physiological and genomic consequences of adrenergic deficiency during embryonic/fetal development in mice: impact on retinoic acid metabolism.
Adrenergic hormones are essential for early heart development. To gain insight into understanding how these hormones influence heart development, we evaluated genomic expression changes in embryonic hearts from adrenergic-deficient and wild-type control mice. To perform this study, we used a mouse model with targeted disruption of the Dopamine β-hydroxylase (Dbh) gene, whose product is responsible for enzymatic conversion of dopamine into norepinephrine. Embryos homozygous for the null allele (Dbh(-/-)) die from heart failure beginning as early as embryonic day 10.5 (E10.5). To assess underlying causes of heart failure, we isolated hearts from Dbh(-/-) and Dbh(+/+) embryos prior to manifestation of the phenotype and examined gene expression changes using genomic Affymetrix 430A 2.0 arrays, which enabled simultaneous evaluation of >22,000 genes. We found that only 22 expressed genes showed a significant twofold or greater change, representing ~0.1% of the total genes analyzed. More than half of these genes are associated with either metabolism (31%) or signal transduction (22%). Remarkably, several of the altered genes encode for proteins that are directly involved in retinoic acid (RA) biosynthesis and transport. Subsequent evaluation showed that RA concentrations were significantly elevated by an average of ~3-fold in adrenergic-deficient (Dbh(-/-)) embryos compared with controls, thereby suggesting that RA may be an important downstream mediator of adrenergic action during embryonic heart development.
Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, Orlando, Florida 32827, USA. kosuala@med.wayne.edu
Kingsley
K
Osuala
Candice N
CN
Baker
Ha-Long
HL
Nguyen
Celines
C
Martinez
David
D
Weinshenker
Steven N
SN
Ebert
D000818:Animals; D053898:Biosynthetic Pathways / Q000235:genetics*; D004299:Dopamine beta-Hydroxylase / Q000172:deficiency / Q000235:genetics*; D004452:Echocardiography; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D006321:Heart / Q000196:embryology*; D006333:Heart Failure / Q000201:enzymology / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D060888:Real-Time Polymerase Chain Reaction; D014212:Tretinoin / Q000378:metabolism*
D014212:Tretinoin; D004299:Dopamine beta-Hydroxylase