Abstract
The all-trans-retinoic acid (atRA) hydroxylase Cyp26a1 is essential for embryonic development and may play a key role in regulating atRA clearance also in adults. We hypothesized that loss of Cyp26a1 activity via inducible knockout in juvenile or adult mice would result in decreased atRA clearance and increased tissue atRA concentrations and atRA-related adverse effects. To test these hypotheses, Cyp26a1 was knocked out in juvenile and adult male and female Cyp26a1 floxed mice using standard Cre-Lox technology and tamoxifen injections. Biochemical and histological methods were used to study the effects of global Cyp26a1 knockout. The Cyp26a1 knockout did not result in consistent histopathological changes in any major organs. Cyp26a1-/- mice gained weight normally and exhibited no adverse phenotypes for up to 1 year after loss of Cyp26a1 expression. Similarly, atRA concentrations were not increased in the liver, testes, spleen, or serum of these mice, and the Cyp26a1 knockout did not cause compensatory induction of lecithin:retinol acetyltransferase (Lrat) or retinol dehydrogenase 11 (Rdh11) mRNA or a decrease in aldehyde dehydrogenase 1a1 (Aldh1a1) mRNA in the liver compared with tamoxifen-treated controls. However, the Cyp26a1-/- mice showed increased bone marrow cellularity and decreased frequency of erythroid progenitor cells in the bone marrow consistent with a retinoid-induced myeloid skewing of hematopoiesis. In addition, the Cyp26a1 knockout decreased clearance of exogenous atRA by 70% and increased atRA half-life 6-fold. These findings demonstrate that despite lacking a major impact on endogenous atRA signaling, Cyp26a1 critically contributes as a barrier for exogenous atRA exposure.
Highlights
The all-trans-retinoic acid hydroxylase Cyp26a1 is essential for embryonic development and may play a key role in regulating atRA clearance in adults
AtRA concentrations were not increased in the liver, testes, spleen, or serum of these mice, and the Cyp26a1 knockout did not cause compensatory induction of lecithin:retinol acetyltransferase (Lrat) or retinol dehydrogenase 11 (Rdh11) mRNA or a decrease in aldehyde dehydrogenase 1a1 (Aldh1a1) mRNA in the liver compared with tamoxifen-treated controls
The RT-PCR analysis suggested that the Cyp26a1ϩ/Ϫ animals had reduced Cyp26a1 mRNA expression compared with Cyp26a1ϩ/ϩ controls (Fig. 1), the expression levels of Cyp26a1 mRNA were highly variable
Summary
The all-trans-retinoic acid (atRA) hydroxylase Cyp26a1 is essential for embryonic development and may play a key role in regulating atRA clearance in adults. We hypothesized that loss of Cyp26a1 activity via inducible knockout in juvenile or adult mice would result in decreased atRA clearance and increased tissue atRA concentrations and atRA-related adverse effects. This is well-demonstrated by the male infertility resulting from vitamin A deficiency and depletion of atRA in the testis after dosing with Aldh1a inhibitors (8), by the teratogenic effects of retinoids (9, 10), and by the development of acute promyelocytic leukemia when retinoic acid receptor is mutated impairing retinoid signaling (11) Despite these wellcharacterized phenotypes of vitamin A and retinoid imbalance and the extensive characterization of generation of atRA gradients during embryonic and fetal development (1, 5), the detailed enzymological processes that regulate tissue-specific concentrations of atRA and retinoid signaling in adult mammals are still not completely understood. The goal of this study was to determine whether the previously shown critical need for Cyp26a1 activity during fetal development (25, 26) extends to a necessity of this enzyme in regulating atRA homeostasis in adult animals
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