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Papers In Press, published online ahead of print December 12, 2001
McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI 53706
Corresponding Author: alshen{at}facstaff.wisc.edu
The microsomal flavoprotein NADPH-cytochrome P450 oxidoreductase (CYPOR) is believed to function as the primary, if not sole, electron donor for the microsomal cytochrome P450 mixed function oxidase system. Development of the mammalian embryo is dependent upon temporally- and spatially- regulated expression of signaling factors, many of which are synthesized and/or degraded via the cytochromes P450 and other pathways involving NADPH-cytochrome P450 oxidoreductase (CYPOR) as the electron donor. Expression of CYPOR as early as the 2-cell stage of embryonic development [TIGR Mouse Gene Index - Version5.0, www.tigr.org/tdb/mgi] suggests that CYPOR is essential for normal cellular functions and/or early embryogenesis. Targeted deletion of the translation start site and membrane-binding domain of CYPOR abolished microsomal CYPOR expression and led to production of a truncated, 66 kDa protein localized to the cytoplasm. Although early embryogenesis was not affected, a variety of embryonic defects was observable by day 10.5 of gestation, leading to lethality by day 13.5. Furthermore, a deficiency of heterozygotes was observed in 2-week old mice as well as late gestational age embryos, suggesting that loss of one CYPOR allele produced some embryonic lethality. CYPOR -/- embryos displayed a marked friability, consistent with defects in cell adhesion. 90% of CYPOR -/- embryos isolated at days 10.5 or 11.5 of gestation could be classified as either Type I, characterized by grossly normal somite formation but having neural tube, cardiac, eye, and limb abnormalities, or Type II, characterized by a generalized retardation of development after approximately day 8.5 of gestation. No CYPOR -/- embryos were observed after day 13.5 of gestation. These studies demonstrate that loss of microsomal CYPOR does not block early embryonic development but is essential for progression past mid-gestation.
J. Biol. Chem, 10.1074/jbc.M111408200
Submitted on November 29, 2001
Revised on December 10, 2001
Accepted on December 11, 2001
Association of multiple developmental defects and embryonic lethality with loss of microsomal NADPH-cytochrome P450 oxidoreductase
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