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Originally published In Press as doi:10.1167/iovs.08-1913 on April 17, 2008
 (Investigative Ophthalmology and Visual Science. 2008;49:3758-3767.)
© 2008 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.08-1913
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Transcriptional Regulation of the Human {alpha}6 Integrin Gene by the Transcription Factor NFI during Corneal Wound Healing

Manon Gaudreault,1,2 François Vigneault,1,2,3 Marie-Eve Gingras,1,2 Steeve Leclerc,1,2 Patrick Carrier,4,5,6 Lucie Germain,4,5,6 and Sylvain L. Guérin1,6,7

1From the Oncology and Molecular Endocrinology Research Center, Centre Hospitalier Universitaire de Québec, CHUL, Québec, Québec, Canada; the 3Department of Genetics, Harvard Medical School, Boston, Massachusetts; 4Laboratoire d’Organogénèse Expérimentale (LOEX), Hôpital du Saint-Sacrement du CHA (Centre Hospitalier Affilié), Québec, Québec, Canada; and the Départements 5de Chirurgie, 6d’Oto-Rhino-Laryngologie et d’Ophtalmologie, and 7d’Anatomie-Physiologie, Faculté de médicine, Université Laval, Québec, Québec, Canada.

PURPOSE. Wound healing of the corneal epithelium is highly influenced by regulation of integrin gene expression. A recent study demonstrated that laminin (LM), a major constituent of the extracellular matrix (ECM), reduces expression of the human {alpha}6 integrin subunit gene by altering the properties of the transcription factor (TF) Sp1. In this work, a target site was identified for the TF nuclear factor I (NFI) on the human {alpha}6 gene, and its regulatory influence was characterized in corneal epithelial cells.

METHODS. Plasmids bearing the {alpha}6 promoter fused to the CAT gene were transfected into human (HCECs) and rabbit (RCECs) corneal epithelial cells grown on LM. The DNA-binding site for NFI in the {alpha}6 promoter was identified by DNase I footprinting. Expression and DNA binding of NFI was monitored by Western blot, RT-PCR, and electrophoretic mobility shift assays (EMSAs), and its function was investigated through RNAi and NFI overexpression assays.

RESULTS. All NFI isoforms were found to be expressed in HCECs and RCECs. Transfection analyses revealed that NFI is a repressor of {alpha}6 expression in both types of cells. LM increases expression of NFI, whereas inhibition of each NFI isoform increases promoter activity suggesting that NFI is a key repressor of {alpha}6 transcription. In addition, the negative influence of NFI appears to be potentiated by the degradation of Sp1 when cells are grown on LM.

CONCLUSIONS. Repression of {alpha}6 expression therefore contributes to the final steps of corneal wound healing by both reducing proliferation and allowing attachment of the epithelium to the basal membrane.






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