The role of β‐carotene‐9′,10′‐oxygenase as a retinoid‐generating enzyme during mammalian embryonic development

Abstract

Vitamin A is an essential nutrient throughout the mammalian lifecycle, and is critical for proper embryonic development. β‐carotene (bC), a provitamin A carotenoid, is the major vitamin A source for most of the world. bC is converted to vitamin A by one of two enzymatic cleavage mechanisms: central cleavage by β‐carotene‐15,15′‐oxygenase (CMO1), or asymmetric cleavage by β‐carotene 9′,10′‐oxygenase (CMO2). CMO1 is thought to be more important for converting bC to vitamin A, while CMO2 functions to clear carotenoids for mitochondrial protection. Both CMO1 and CMO2 are expressed in the developing tissues, and recent work has demonstrated that CMO1 can cleave bC locally in embryos to generate vitamin A for normal development. When CMO1+/−RBP−/− dams were fed a vitamin A‐deficient diet during pregnancy, embryos were grossly malformed (eye defects, peripheral edema, and exencephaly). Supplementation of CMO1+/−RBP−/− dams with bC from 6.5–9.5 days post coitum rescued the malformations of this strain. To investigate whether CMO2 may still function as a retinoid‐generating enzyme in vivo, at least in the embryo, we fed CMOI−/−RBP−/− dams a vitamin A‐deficient diet during pregnancy and observed that bC supplementation improved the vitamin A deficiency symptoms of the double knockout embryos. We next generated triple knockout mice lacking CMO1, RBP, and CMO2. Experiments are ongoing to maintain the triple knockout dams on a vitamin A‐deficient diet throughout pregnancy and monitor the frequency of embryonic malformations, as well as maternal and embryonic vitamin A levels. These experiments will shed more light on the role of CMO2 during embryonic development.Grant Funding Source : NIH