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Molecular and Cellular Biology, May 2009, p. 2716-2729, Vol. 29, No. 10
0270-7306/09/$08.00+0     doi:10.1128/MCB.01638-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Cholesterol Metabolism: the Main Pathway Acting Downstream of Cytochrome P450 Oxidoreductase in Skeletal Development of the Limb{triangledown} ,{dagger}

Katy Schmidt,1* Catherine Hughes,2 J. A. Chudek,3 Simon R. Goodyear,4 Richard M. Aspden,4 Richard Talbot,5 Thomas E. Gundersen,6 Rune Blomhoff,6 Colin Henderson,2 C. Roland Wolf,2 and Cheryll Tickle1*

Division of Cell and Developmental Biology, Wellcome Trust Biocentre, University of Dundee, Dundee DD1 5EH, United Kingdom,1 Cancer Research UK, Molecular Pharmacology Unit, Biomedical Research Center, Ninewells Hospital and Medical School, Dundee DD1 9SY, United Kingdom,2 Division of Biological Chemistry, Wellcome Trust Biocentre, University of Dundee, Dundee DD1 5EH, United Kingdom,3 Division of Applied Medicine, IMS Building, Foresterhill, Aberdeen AB25 2ZD, United Kingdom,4 Roslin Institute, Edinburgh EH25 9PS, United Kingdom,5 Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway6

Received 21 October 2008/ Returned for modification 14 December 2008/ Accepted 21 February 2009

Cytochrome P450 oxidoreductase (POR) is the obligate electron donor for all microsomal cytochrome P450 enzymes, which catalyze the metabolism of a wide spectrum of xenobiotic and endobiotic compounds. Point mutations in POR have been found recently in patients with Antley-Bixler-like syndrome, which includes limb skeletal defects. In order to study P450 function during limb and skeletal development, we deleted POR specifically in mouse limb bud mesenchyme. Forelimbs and hind limbs in conditional knockout (CKO) mice were short with thin skeletal elements and fused joints. POR deletion occurred earlier in forelimbs than in hind limbs, leading additionally to soft tissue syndactyly and loss of wrist elements and phalanges due to changes in growth, cell death, and skeletal segmentation. Transcriptional analysis of E12.5 mouse forelimb buds demonstrated the expression of P450s involved in retinoic acid, cholesterol, and arachidonic acid metabolism. Biochemical analysis of CKO limbs confirmed retinoic acid excess. In CKO limbs, expression of genes throughout the whole cholesterol biosynthetic pathway was upregulated, and cholesterol deficiency can explain most aspects of the phenotype. Thus, cellular POR-dependent cholesterol synthesis is essential during limb and skeletal development. Modulation of P450 activity could contribute to susceptibility of the embryo and developing organs to teratogenesis.

* Corresponding author. Mailing address for Cheryll Tickle: Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, United Kingdom. Phone: 44-(0)1225-385015. Fax: 44-(0)1225-386779. E-mail: cat24{at}bath.ac.uk. Mailing address for Katy Schmidt: Department of Biochemistry, University of Bristol, University Walk, Bristol BS8 1TD, United Kingdom. Phone: 44-(0)117-3312163. Fax: 44-(0)117-3312168. E-mail: k.schmidt{at}bristol.ac.uk

{triangledown} Published ahead of print on 9 March 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, May 2009, p. 2716-2729, Vol. 29, No. 10
0270-7306/09/$08.00+0     doi:10.1128/MCB.01638-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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