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J. Biol. Chem., Vol. 281, Issue 4, 1992-1999, January 27, 2006

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Hoxd13 and Hoxa13 Directly Control the Expression of the EphA7 Ephrin Tyrosine Kinase Receptor in Developing Limbs^*

Valentina Salsi and Vincenzo Zappavigna1

From the Department of Animal Biology, University of Modena and Reggio Emilia, Via G. Campi 213/d, Modena 41100, Italy and the Department of Cell and Developmental Biology, Cornell University Weill Medical School, New York, New York 10021

Hoxa and Hoxd genes, related to the Drosophila Abd-B gene, display regionally restricted expression patterns and are necessary for the formation of the limb skeletal elements. Hox genes encode transcription factors, which are supposed to control the expression of a series of downstream target genes, whose nature has remained largely elusive. Several genes were identified that are differentially expressed in relation to Hox gene activity; few studies, however, explored their direct regulation by Hox proteins. Ephrin tyrosine kinase receptors and ephrins have been proposed as Hox targets, and recently, evidence was gained for their role in limb development. The expression of the EphA7 gene in developing limbs was shown to correlate with the expression of Hoxa13 and Hoxd13; however, its direct regulation by these genes has never been assessed. We have characterized the EphA7 promoter region and show that it contains multiple binding sites for paralog group 13 Hox proteins. We found that one of these sites is bound in vivo by HOXA13 and HOXD13 and by endogenous Hoxd13 in developing mouse limbs. Moreover, we show that HOXD13 and HOXA13 activate transcription from the EphA7 promoter and that a mutation of the HOXA13/HOXD13 binding site was sufficient to abolish activation. Conversely, the HOXD13(147L) mutation, identified in patients displaying a novel brachydactyly-polydactyly syndrome, does not bind to in vivo, and fails to transactivate the EphA7 promoter. These results establish that EphA7 is a direct downstream target of Hoxd13 and Hoxa13 during limb development, thus providing further insight into the regulatory networks that control limb patterning.

Received for publication, October 5, 2005 , and in revised form, November 10, 2005.

^* This work was supported by grants from the Italian Association for Cancer Research, and the Italian Association for the Study of Malformations (to V. Z.). 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: Dept. of Animal Biology, University of Modena and Reggio Emilia, Via G. Campi 213/d, Modena 41100, Italy. Tel.: 39-059-2055537; Fax: 39-059-2055548; E-mail: zappavigna.vincenzo{at}unimore.it.

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