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Molecular and Cellular Biology, January 2008, p. 315-325, Vol. 28, No. 1
0270-7306/08/$08.00+0     doi:10.1128/MCB.01168-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Identification and Analysis of a Conserved Tcfap2a Intronic Enhancer Element Required for Expression in Facial and Limb Bud Mesenchyme{triangledown} ,{dagger}

Weiguo Feng,1 Jian Huang,1,2 Jian Zhang,2,{ddagger} and Trevor Williams1,2*

Department of Craniofacial Biology and Department of Cell and Developmental Biology, UCHSC at Fitzsimons, Mailstop 8120, P.O. Box 6511, Aurora, Colorado 80045,1 Department of Molecular, Cellular, and Developmental Biology, Yale University, 266 Whitney Ave., New Haven, Connecticut 065112

Received 29 June 2007/ Returned for modification 23 July 2007/ Accepted 18 October 2007

Tcfap2a, the gene encoding the mouse AP-2{alpha} transcription factor, is required for normal development of multiple structures during embryogenesis, including the face and limbs. Using comparative sequence analysis and transgenic-mouse experiments we have identified an intronic enhancer within this gene that directs expression to the face and limb mesenchyme. There are two conserved sequence blocks within this intron, and the larger of these directs tissue-specific activity and is found in all vertebrate Tcfap2a genes analyzed. To assess the role of the enhancer in regulating endogenous mouse Tcfap2a expression, we have deleted this cis-regulatory sequence from the genome. Loss of this element severely impairs Tcfap2a expression in the limb bud mesenchyme but generates only a modest reduction in the facial mesenchyme. The reduction in Tcfap2a transcription is accompanied by altered patterning of the forelimb, resulting in postaxial polydactyly. These results indicate that the major role for this enhancer resides within the limb bud, and it serves to maintain a level of Tcfap2a expression that limits the size of the hand plate and the associated number of digit primordia. The potential role of this cis-acting sequence in modeling the size and shape of the face and limbs during evolution is discussed.

* Corresponding author. Mailing address: Department of Craniofacial Biology and Department of Cell and Developmental Biology, UCHSC at Fitzsimons, Mailstop 8120, P.O. Box 6511, Aurora, CD 80045. Phone: (303) 724 4571. Fax: (303) 724 4580. E-mail: trevor.williams{at}uchsc.edu

{triangledown} Published ahead of print on 5 November 2007.

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

{ddagger} Present address: College of Life Science, Hunan Normal University, Changsha, Hunan 410081, People's Republic of China.

Molecular and Cellular Biology, January 2008, p. 315-325, Vol. 28, No. 1
0270-7306/08/$08.00+0     doi:10.1128/MCB.01168-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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