Does beta‐carotene‐9′,10′‐oxygenase (CMO2) generate retinoic acid during embryonic development?

Abstract

Vitamin A is an essential nutrient throughout the mammalian lifecycle, especially for normal embryonic development. Most of the world relies on β‐carotene (bC), a provitamin A carotenoid, as its main vitamin A source. 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). ~95% of bC conversion to vitamin A is attributed to CMO1, while CMO2, a mitochondrial enzyme, is thought to contribute minimally to vitamin A production in vivo. Both CMO1 and CMO2 are expressed in the developing tissues, and local bC cleavage by embryonic CMO1 can generate adequate vitamin A for normal development. When CMO1−/−RBP−/− dams were fed a vitamin A‐deficient diet during pregnancy, embryos developed gross malformations including eye defects, peripheral edema, and exencephaly. Supplementation of CMO1−/−RBP−/− dams with bC from 6.5–9.5 days post coitum partly improved the vitamin A deficiency symptoms of the double knockout embryos, despite the lack of CMO1. To determine whether bC cleavage by CMO2 contributed to this improvement, triple knockout mice (CMO1−/−RBP−/− CMO2−/−) were also generated, and analyzed under the same dietary regimen. The frequency of defects of CMO1−/−RBP−/−CMO2−/− embryos from dams fed a vitamin A‐deficient diet was similar to that observed in double‐knockout embryos. Experiments are ongoing to investigate whether the embryonic defects of triple knockout embryos can be improved by bC supplementation from 6.5–9.5 dpc. These experiments will shed more light on the role of CMO2 as a potential retinoic acid‐generating enzyme during embryonic development.Grant Funding Source: NIH; Gates Foundation