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Originally published In Press as doi:10.1074/jbc.M111408200 on December 12, 2001

J. Biol. Chem., Vol. 277, Issue 8, 6536-6541, February 22, 2002
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Association of Multiple Developmental Defects and Embryonic Lethality with Loss of Microsomal NADPH-Cytochrome P450 Oxidoreductase*

Anna L. ShenDagger , Kathleen A. O'LearyDagger , and Charles B. Kasper§

From the McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, Wisconsin 53706-1599

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 as the electron donor. Expression of CYPOR as early as the two-cell stage of embryonic development (The Institute for Genomic Research Mouse Gene Index, version 5.0, 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. Ninety percent 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.

* This work was supported by Grants CA22484 and CA07175 from the National Institutes of Health (NIH). This study made use of the Advanced Microscopy Facility and Services Core, University of Wisconsin-Madison Environmental Health Sciences Center, with support through Center Grant P30 ES09090-04 from the NIEHS, NIH.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Both authors contributed equally to this work.

§ To whom correspondence should be addressed: 421 McArdle Laboratory, 1400 University Ave., Madison, WI 53706. Tel.: 608-262-6952; Fax: 608-262-2824; E-mail: kasper@oncology.wisc.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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