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J. Biol. Chem., Vol. 280, Issue 4, 3012-3021, January 28, 2005

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Dominant-negative Retinoic Acid Receptors Elicit Epidermal Defects through a Non-canonical Pathway^*

Chang Feng Chen¶ and David Lohnes, A chercheur bourcier (Senior) of the Fonds de la Recherches en Sante de Quebec||**

From the Division of Experimental Medicine, Department of Medicine, McGill University, the Clinical Research Institute of Montreal, Montreal, Quebec H2W 1R7, and the ^||Department of Molecular Biology, University of Montreal, Montreal K1H 8M5, Canada

Previous work has shown that a dominant-negative retinoic acid receptor (dnRAR), expressed under the K14 promoter, causes severe epidermal defects. Similar defects are, however, not seen in RAR double null mutant mice, which lack the entire complement of RARs expressed in the epidermis. To investigate the mechanism of action of these dominant-negative receptors, dnRAR or a DNA binding-deficient variant, dnRAR^DBD, were targeted to the basal epidermis. Expression of either receptor type led to similar epidermal phenotypes suggesting that both RAR mutants acted through a common mechanism. The epidermal phenotype was reminiscent of defects seen in p63^-/- mice. Consistent with this, reduced p63 expression was observed in transgenic offspring expressing either RAR mutant, suggesting that down-regulation of p63 might underlie the effects of these receptors on epidermal development. By contrast, expression of p63 in the epidermis of RAR^-/- offspring was unaffected, indicating that RARs were not essential for p63 expression. These findings suggest that dnRARs may impact on epidermal development through one or more non-canonical pathways, which are independent of receptor-DNA interaction.

Received for publication, October 8, 2004

^* This work was supported in part by the National Cancer Institute of Canada with funds from the Canadian Cancer Society. 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.

^¶ Supported by a scholarship from the Cancer Research Society, Inc.

^** To whom correspondence should be addressed: Dept. of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Rd., Ontario K1H 8M5, Canada. Tel.: 613-562-5800 (ext. 8684); Fax: 613-562-5434; E-mail: dlohnes{at}uottawa.ca.

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