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J. Biol. Chem., Vol. 280, Issue 7, 5828-5835, February 18, 2005

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The Murine Cyp1a1 Gene Is Expressed in a Restricted Spatial and Temporal Pattern during Embryonic Development^*

Sandra J. Campbell, Colin J. Henderson, Daniel C. Anthony, Duncan Davidson¶, A. John Clark||, and C. Roland Wolf**

From the Cancer Research UK Molecular Pharmacology Unit, Biomedical Research Centre, University of Dundee, Level 5, Ninewells Hospital and Medical School, Dundee DD1 9SY, United Kingdom, the ^¶Medical Research Council Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, United Kingdom, the ^||University of Edinburgh, Agriculture and Food Research Council Institute of Animal Physiology and Genetics Research, Roslin, Edinburgh EH25 9PS, United Kingdom, and Experimental Neuropathology, Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, United Kingdom

In adult mice the cytochrome P450 Cyp1a1 gene is not constitutively expressed but is highly inducible by foreign compounds acting through the aryl hydrocarbon (Ah) receptor. However, the expression profile of the Cyp1a1 gene in the developing embryo is not well under-stood. Using established transgenic mouse lines where 8.5 kb of the rat CYP1A1 promoter is cloned upstream of the lacZ reporter gene (1), we describe the expression of the CYP1A1-driven reporter gene in all tissues through-out stages E7–E14 of embryonic development. In contrast to the absence of constitutive Cyp1a1 and lacZ transgene expression in tissues of the adult mouse, a constitutive cell-specific and time-dependent pattern of CYP1A1 promoter activity was observed in the embryo. This expression pattern was confirmed as reflecting the endogenous gene by measuring Cyp1a1 mRNA levels and protein expression by immunohistochemistry. The number of cells displaying endogenous CYP1A1 activity could be increased in the embryo upon xenobiotic challenge, but only within areas where the CYP1A1 promotor was already active. When reporter mice were bred onto a genetic background expressing a lower affinity form of the Ah receptor (DBA allele), transgene and murine Cyp1a1 protein expression were both attenuated in the adult mouse liver upon xenobiotic challenge. By comparison, constitutive CYP1A1 promoter activity in the embryo was identical in the presence of either the high or low affinity Ah receptor. These novel data suggest that the Cyp1a1 protein may play a role in murine development and that regulation of the Cyp1a1 gene during this period is either through the action of a high affinity Ah receptor ligand or by an alternative regulatory pathway.

Received for publication, November 15, 2004

^* This work was supported by the Biotechnology and Biological Sciences Research Council. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

John Clark sadly died in June of 2004. This paper is dedicated to him.

^** To whom correspondence should be addressed. Tel.: 441382-632621; Fax: 441382-669993; E-mail: roland.wolf{at}cancer.org.uk.

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