Rescue of cytochrome P450 oxidoreductase (Por) mouse mutants reveals functions in vasculogenesis, brain and limb patterning linked to retinoic acid homeostasis

Vanessa Ribes, Diana M.E. Otto, Leslie Dickmann, Katy Schmidt, Brigitte Schuhbaur, Colin Henderson, Rune Blomhoff, C. Roland Wolf, Cheryll Tickle (Lead / Corresponding author), Pascal Dollé (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

47 Citations (Scopus)

Abstract

Cytochrome P450 oxidoreductase (POR) acts as an electron donor for all cytochrome P450 enzymes. Knockout mouse Por-/- mutants, which are early embryonic (E9.5) lethal, have been found to have overall elevated retinoic acid (RA) levels, leading to the idea that POR early developmental function is mainly linked to the activity of the CYP26 RA-metabolizing enzymes (Otto et al., Mol. Cell. Biol. 23, 6103-6116). By crossing Por mutants with a RA-reporter lacZ transgene, we show that Por-/- embryos exhibit both elevated and ectopic RA signaling activity e.g. in cephalic and caudal tissues. Two strategies were used to functionally demonstrate that decreasing retinoid levels can reverse Por-/- phenotypic defects, (i) by culturing Por-/- embryos in defined serum-free medium, and (ii) by generating compound mutants defective in RA synthesis due to haploinsufficiency of the retinaldehyde dehydrogenase 2 (Raldh2) gene. Both approaches clearly improved the Por-/- early phenotype, the latter allowing mutants to be recovered up until E13.5. Abnormal brain patterning, with posteriorization of hindbrain cell fates and defective mid- and forebrain development and vascular defects were rescued in E9.5 Por-/- embryos. E13.5 Por-/-; Raldh2+/- embryos exhibited abdominal/caudal and limb defects that strikingly phenocopy those of Cyp26a1-/- and Cyp26b1-/- mutants, respectively. Por-/-; Raldh2+/- limb buds were truncated and proximalized and the anterior-posterior patterning system was not established. Thus, POR function is indispensable for the proper regulation of RA levels and tissue distribution not only during early embryonic development but also in later morphogenesis and molecular patterning of the brain, abdominal/caudal region and limbs.

Original languageEnglish
Pages (from-to)66-81
Number of pages16
JournalDevelopmental Biology
Volume303
Issue number1
DOIs
Publication statusPublished - 1 Mar 2007

Keywords

  • Brain patterning
  • CYP enzymes
  • Limb development
  • P450 cytochromes
  • POR
  • Retinoids
  • Vasculogenesis

Fingerprint

Dive into the research topics of 'Rescue of cytochrome P450 oxidoreductase (Por) mouse mutants reveals functions in vasculogenesis, brain and limb patterning linked to retinoic acid homeostasis'. Together they form a unique fingerprint.

Cite this