Identification of novel roles of the cytochrome p450 system in early embryogenesis: effects on vasculogenesis and retinoic Acid homeostasis.
The cytochrome P450-dependent monooxygenase system catalyzes the metabolism of xenobiotics and endogenous compounds, including hormones and retinoic acid. In order to establish the role of these enzymes in embryogenesis, we have inactivated the system through the deletion of the gene for the electron donor to all microsomal P450 proteins, cytochrome P450 reductase (Cpr). Mouse embryos homozygous for this deletion died in early to middle gestation (approximately 9.5 days postcoitum [dpc]) and exhibited a number of novel phenotypes, including the severe inhibition of vasculogenesis and hematopoiesis. In addition, defects in the brain, limbs, and cell types where CPR was shown to be expressed were observed. Some of the observed abnormalities have been associated with perturbations in retinoic acid homeostasis in later embryogenesis. Consistent with this possibility, embryos at 9.5 dpc had significantly elevated levels of retinoic acid and reduced levels of retinol. Further, some of the observed phenotypes could be either reversed or exacerbated by decreasing or increasing maternal retinoic acid exposure, respectively. Detailed analysis demonstrated a close relationship between the observed phenotype and the expression of genes controlling vasculogenesis. These data demonstrate that the cytochrome P450 system plays a key role in early embryonic development; this process appears to be, at least in part, controlled by regional concentrations of retinoic acid and has profound effects on blood vessel formation.
Otto
Diana M E
DM
Cancer Research UK, Molecular Pharmacology Unit, Biomedical Research Centre, Ninewells Hospital and Medical School, Dundee DD1 9SY, United Kingdom.
Henderson
Colin J
CJ
Carrie
Dianne
D
Davey
Megan
M
Gundersen
Thomas E
TE
Blomhoff
Rune
R
Adams
Ralf H
RH
Tickle
Cheryll
C
Wolf
C Roland
CR
D000818:Animals; D001808:Blood Vessels / Q000002:abnormalities / Q000196:embryology*; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D004622:Embryo, Mammalian / Q000098:blood supply / Q000201:enzymology*; D005313:Fetal Death / Q000235:genetics; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D006706:Homeostasis / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D008861:Microsomes / Q000502:physiology; D009251:NADPH-Ferrihemoprotein Reductase / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D018168:Receptors, Retinoic Acid / Q000235:genetics; D014212:Tretinoin / Q000378:metabolism* / Q000494:pharmacology; D014801:Vitamin A / Q000378:metabolism
C496457:Fgf8 protein, mouse; D018168:Receptors, Retinoic Acid; C082927:retinoic acid binding protein I, cellular; C082928:retinoic acid binding protein II, cellular; D014801:Vitamin A; D051524:Fibroblast Growth Factor 8; D014212:Tretinoin; D005346:Fibroblast Growth Factors; D003577:Cytochrome P-450 Enzyme System; D009251:NADPH-Ferrihemoprotein Reductase