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Molecular and Cellular Biology, January 2004, p. 245-257, Vol. 24, No. 1
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.1.245-257.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Transcription Factors Pax6 and AP-2{alpha} Interact To Coordinate Corneal Epithelial Repair by Controlling Expression of Matrix Metalloproteinase Gelatinase B

Jeremy M. Sivak,1 Judith A. West-Mays,2 Amy Yee,3 Trevor Williams,4 and M. Elizabeth Fini5*

Evelyn F. and William L. McKnight Vision Research Center, Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, Florida 33136,5 Wellcome Trust/Cancer Research UK Institute of Cancer and Developmental Biology, University of Cambridge, Cambridge CB2 1QR, United Kingdom,1 Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario L8N 3Z5, Canada,2 Department of Biochemistry, Tufts University School of Medicine, Boston, Massachusetts 02114,3 Department of Craniofacial Biology and Cellular and Developmental Biology, University of Colorado Health Sciences Center, Denver, Colorado 802624

Received 21 February 2003/ Returned for modification 7 April 2003/ Accepted 2 September 2003

Pax6 is a paired box containing transcription factor that resides at the top of a genetic hierarchy controlling eye development. It continues to be expressed in tissues of the adult eye, but its role in this capacity is unclear. Pax6 is present in the adult corneal epithelium, and we showed that the amount of Pax6 is increased at the migrating front as the epithelium resurfaces the cornea after injury (J. M. Sivak, R. Mohan, W. B. Rinehart, P. X. Xu, R. L. Maas, and M. E. Fini, Dev. Biol. 222:41-54, 2000). We also showed that Pax6 controls activity of the transcriptional promoter for the matrix metalloproteinase, gelatinase B (gelB; MMP-9) in cell culture transfection studies. gelB expression is turned on at the migrating epithelial front in the cornea, and it coordinates and effects aspects of epithelial regeneration (R. Mohan, S. K. Chintala, J. C. Jung, W. V. Villar, F. McCabe, L. A. Russo, Y. Lee, B. E. McCarthy, K. R. Wollenberg, J. V. Jester, M. Wang, H. G. Welgus, J. M. Shipley, R. M. Senior, and M. E. Fini, J. Biol. Chem. 277:2065-2072). We define here two positively acting Pax6 response elements in the gelB promoter. Pax6 binds directly to one of these sites through the paired DNA-binding domain. It binds the second site indirectly by interaction with AP-2{alpha}, a transcription factor that also exerts control over eye development. Pax6 control of gelB expression was examined in vivo by using a corneal reepithelialization model in mice heterozygous for a Pax6 paired-domain mutation (Sey+/-). A reduced Pax6 dosage in these mice resulted in a loss of gelB expression at the migrating epithelial front. This effect was correlated with an increase in inflammation and the rate of reepithelialization, a finding consistent with the phenotype of gelB knockout mice. Together, these data indicate that Pax6 controls activity of the gelB promoter through cooperative interactions with AP-2{alpha} and support an active role for Pax6 in maintenance and repair of the adult corneal epithelium.

* Corresponding author. Mailing address: McKnight Vision Research Center, Bascom Palmer Eye Institute, University of Miami School of Medicine, 1638 NW 10th Ave., Miami, FL 33136. Phone: (305) 326-6046. Fax: (305) 326-6306. E-mail: efini{at}med.miami.edu.

Molecular and Cellular Biology, January 2004, p. 245-257, Vol. 24, No. 1
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.1.245-257.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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