Knockout of Cyp26a1 and Cyp26b1 during postnatal life causes reduced lifespan, dermatitis, splenomegaly, and systemic inflammation in mice

Jessica M. Snyder, Guo Zhong, Cathryn Hogarth, Weize Huang, Traci Topping, Jeffrey LaFrance, Laura Palau, Lindsay C. Czuba, Michael Griswold, Gabriel Ghiaur, Nina Isoherranen

Research output: Contribution to journalArticlepeer-review

Abstract

All-trans-retinoic acid (atRA), the active metabolite of vitamin A, is an essential signaling molecule in all chordates. Global knockouts of the atRA clearing enzymes Cyp26a1 or Cyp26b1 are embryonic lethal. In adult rodents, inhibition of Cyp26a1 and Cyp26b1 increases atRA concentrations and signaling. However, postnatal knockout of Cyp26a1 does not cause a severe phenotype. We hypothesized that Cyp26b1 is the main atRA clearing Cyp in postnatal mammals. This hypothesis was tested by generating tamoxifen-inducible knockout mouse models of Cyp26b1 alone or with Cyp26a1. Both mouse models showed dermatitis, blepharitis, and splenomegaly. Histology showed infiltration of inflammatory cells including neutrophils and T lymphocytes into the skin and hyperkeratosis/hyperplasia of the nonglandular stomach. The mice lacking both Cyp26a1 and Cyp26b1 also had a reduced lifespan, failed to gain weight, and showed fat atrophy. There were significant changes in vitamin A homeostasis. Postnatal knockout of Cyp26b1 resulted in increased atRA concentrations in the skin while the postnatal knockout of both Cyp26a1 and Cyp26b1 resulted in increased atRA concentrations in the liver, serum, skin, spleen, and intestines. This study demonstrates the paramount role of Cyp26b1 in regulating retinoid homeostasis in postnatal life.

Original languageEnglish (US)
Pages (from-to)15788-15804
Number of pages17
JournalFASEB Journal
Volume34
Issue number12
DOIs
StatePublished - Dec 2020

Keywords

  • cytochrome P450
  • dermatitis
  • inflammation
  • retinoic acid
  • vitamin A

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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