TY - JOUR T1 - Knockout of Cyp26a1 and Cyp26b1 during post-natal life causes reduced lifespan, dermatitis, splenomegaly and systemic inflammation in mice JF - bioRxiv DO - 10.1101/2020.07.09.196170 SP - 2020.07.09.196170 AU - Jessica M Snyder AU - Guo Zhong AU - Cathryn Hogarth AU - Weize Huang AU - Traci Topping AU - Jeffrey LaFrance AU - Laura Palau AU - Lindsay C Czuba AU - Michael Griswold AU - Gabriel Ghiaur AU - Nina Isoherranen Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/07/09/2020.07.09.196170.abstract N2 - All-trans-retinoic acid (atRA), the active metabolite of vitamin A, is an essential signaling molecule. Global knockout of the atRA clearing enzymes Cyp26a1 or Cyp26b1 is embryonic lethal. In adults, inhibition of Cyp26a1 and Cyp26b1 increases atRA concentrations and signaling. However, post-natal knockout of Cyp26a1 does not cause a severe phenotype. We hypothesized that Cyp26b1 is the main atRA clearing Cyp in post-natal 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 non-glandular stomach. The mice lacking both Cyp26a1 and Cyp26b1 also failed to gain weight and showed fat atrophy. There were significant changes in vitamin A homeostasis demonstrating the paramount role of Cyp26b1 in regulating retinoid homeostasis in post-natal life.Competing Interest StatementGG is an author on a patent application for the use of IRX195183. NI is an author on US patent 9963439 on inhibitors of P450 26 ER -