Otx2 is a member of homeodomain-containing transcription factors and is essential for eye morphogenesis in mice. Here we show the expression of OTX2, the human Counterpart of Otx2, in cell lines of retinal pigment epithelium (RPE) and in Y79 retinoblastoma cells that exhibit the property of presumptive RPE. These RPE cells express DOPAchrome tautomerase (DCT) that is an enzyme involved in melanin biosynthesis. DCT may contribute to the homeostasis of RPE by detoxifying DOPA-derived metabolites. OTX2 binds to the DCT gene promoter in vivo, as judged by chromatin immunoprecipitation assays. Furthermore, repression of endogenous OTX2 expression in Y79 cells by an anti-sense OTX2 oligonucleotide resulted in the decrease of DCT protein contents. Transient expression assays revealed that OTX2 activated the DCT gene promoter through the OTX-2-binding site in an RPE-specific manner. Therefore, OTX2 may regulate RPE-specific target genes, such as DCT, thereby maintaining the homeostasis of RPE. (C) 2002 Elsevier Science (USA). All rights reserved.