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J. Biol. Chem., Vol. 282, Issue 41, 30171-30180, October 12, 2007

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Connexin Levels Regulate Keratinocyte Differentiation in the Epidermis^*

From the Departments of Anatomy and Cell Biology and Physiology and Pharmacology, The University of Western Ontario, London, Ontario, N6A 5C1, Canada

To understand the role of connexin43 (Cx43) in epidermal differentiation, we reduced Cx43 levels by RNA-mediated interference knockdown and impaired its functional status by overexpressing loss-of-function Cx43 mutants associated with the human disease oculodentodigital dysplasia (ODDD) in rat epidermal keratinocytes. When Cx43 expression was knocked down by 50-75%, there was a coordinate 55-65% reduction in Cx26 level, gap junction-based dye coupling was reduced by 60%, and transepithelial resistance decreased. Importantly, the overall growth and differentiation of Cx43 knockdown organotypic epidermis was severely impaired as revealed by alterations in the levels of the differentiation markers loricrin and involucrin and by reductions in vital and cornified layer thicknesses. Conversely, although the expression of Cx43 mutants reduced the coupling status of rat epidermal keratinocytes by 80% without altering the levels of endogenous Cx43 or Cx26, their ability to differentiate was not altered. In addition, we used a mouse model of ODDD and found that newborn mice harboring the loss-of-function Cx43^G60S mutant had slightly reduced Cx43 levels, whereas Cx26 levels, epidermis differentiation, and barrier function remained unaltered. This properly differentiated epidermis was maintained even when Cx43 and Cx26 levels decreased by more than 70% in 3-week-old mutant mice. Our studies indicate that Cx43 and Cx26 collectively co-regulate epidermal differentiation from basal keratinocytes but play a more minimal role in the maintenance of established epidermis. Altogether, these studies provide an explanation as to why the vast majority of ODDD patients, where Cx43 function is highly compromised, do not suffer from skin disease.

Received for publication, May 1, 2007 , and in revised form, August 1, 2007.

^* This work was supported by Canadian Institutes of Health Research (CIHR)-Strategic Training Program (to S. L. and A. M.) and CIHR grants (to D. W. L. and G. M. K.). 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.

¹ To whom correspondence should be addressed: The University of Western Ontario, Dental Science Bldg. 00077, London, Ontario, N6A 5C1, Canada. Tel.: 519-661-2111 (ext. 86827); Fax: 519-850-2562; E-mail: dale.laird{at}schulich.uwo.ca.

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