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Molecular and Cellular Biology, January 2009, p. 357-377, Vol. 29, No. 2
0270-7306/09/$08.00+0     doi:10.1128/MCB.01385-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Role of the Molybdoflavoenzyme Aldehyde Oxidase Homolog 2 in the Biosynthesis of Retinoic Acid: Generation and Characterization of a Knockout Mouse{triangledown} ,{dagger}

Mineko Terao,1,# Mami Kurosaki,1,# Maria Monica Barzago,1,# Maddalena Fratelli,1 Renzo Bagnati,2 Antonio Bastone,1 Chiara Giudice,3 Eugenio Scanziani,3 Alessandra Mancuso,4,5 Cecilia Tiveron,4,6 and Enrico Garattini1*

Laboratory of Molecular Biology, Department of Biochemistry and Molecular Pharmacology,1 Department of Environmental Health, Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156 Milan, Italy,2 Dipartimento di Patologia Animale, Igiene e Sanità Pubblica Veterinaria, Sezione di Anatomia Patologica Veterinaria e Patologia Aviare, Facoltà di Medicina Veterinaria, Università degli Studi di Milan, Via Celoria 10, 20133 Milan, Italy,3 Centro Ricerca Sperimentale, Istituto Regina Elena, Via delle Messi d'Oro, 156, 00158 Rome, Italy,4 Università Cattolica del Sacro Cuore, Largo Gemelli 8, 00168 Rome, Italy,5 European Brain Research Institute (E.B.R.I.), Rita Levi-Montalcini Foundation, Via del Fosso di Fiorano 64/65, 00143 Rome, Italy6

Received 3 September 2008/ Returned for modification 28 September 2008/ Accepted 26 October 2008

The mouse aldehyde oxidase AOH2 (aldehyde oxidase homolog 2) is a molybdoflavoenzyme. Harderian glands are the richest source of AOH2, although the protein is detectable also in sebaceous glands, epidermis, and other keratinized epithelia. The levels of AOH2 in the Harderian gland and skin are controlled by genetic background, being maximal in CD1 and C57BL/6 and minimal in DBA/2, CBA, and 129/Sv strains. Testosterone is a negative regulator of AOH2 in Harderian glands. Purified AOH2 oxidizes retinaldehyde into retinoic acid, while it is devoid of pyridoxal-oxidizing activity. Aoh2–/– mice, the first aldehyde oxidase knockout animals ever generated, are viable and fertile. The data obtained for this knockout model indicate a significant role of AOH2 in the local synthesis and biodisposition of endogenous retinoids in the Harderian gland and skin. The Harderian gland's transcriptome of knockout mice demonstrates overall downregulation of direct retinoid-dependent genes as well as perturbations in pathways controlling lipid homeostasis and cellular secretion, particularly in sexually immature animals. The skin of knockout mice is characterized by thickening of the epidermis in basal conditions and after UV light exposure. This has correlates in the corresponding transcriptome, which shows enrichment and overall upregulation of genes involved in hypertrophic responses.

* Corresponding author. Mailing address: Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri, via La Masa 19, 20156 Milan, Italy. Phone: 39-02-39014533. Fax: 39-02-3546277. E-mail: egarattini{at}marionegri.it

{triangledown} Published ahead of print on 3 November 2008.

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

# M.T., M.K., and M.M.B. contributed equally to this work.

Molecular and Cellular Biology, January 2009, p. 357-377, Vol. 29, No. 2
0270-7306/09/$08.00+0     doi:10.1128/MCB.01385-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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