Transcription Factors Pax6 and AP-2alpha Interact To Coordinate Corneal Epithelial Repair by Controlling Expression of Matrix Metalloproteinase Gelatinase B.
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. 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. 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-2alpha, 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-2alpha and support an active role for Pax6 in maintenance and repair of the adult corneal epithelium.
Sivak
Jeremy M
JM
Evelyn F. and William L. McKnight Vision Research Center, Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, Florida 33136, USA.
West-Mays
Judith A
JA
Yee
Amy
A
Williams
Trevor
T
Fini
M Elizabeth
ME
D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019573:Epithelium, Corneal / Q000293:injuries* / Q000378:metabolism; D005136:Eye Proteins; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000378:metabolism*; D014945:Wound Healing / Q000502:physiology*
D004268:DNA-Binding Proteins; D005136:Eye Proteins; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins; C493668:Tfap2a protein, mouse; D050656:Transcription Factor AP-2; D014157:Transcription Factors; D020780:Matrix Metalloproteinase 9