The Microphthalmia Transcription Factor (Mitf) Controls Expression of the Ocular Albinism Type 1 Gene: Link between Melanin Synthesis and Melanosome Biogenesis

Abstract

Melanogenesis is the process that regulates skin and eye pigmentation. Albinism, a genetic disease causing pigmentation defects and visual disorders, is caused by mutations in genes controlling either melanin synthesis or melanosome biogenesis. Here we show that a common transcriptional control regulates both of these processes. We performed an analysis of the regulatory region of Oa1, the murine homolog of the gene that is mutated in the X-linked form of ocular albinism, as Oa1's function affects melanosome biogenesis. We demonstrated that Oa1 is a target of Mitf and that this regulatory mechanism is conserved in the human gene. Tissue-specific control of Oa1 transcription lies within a region of 617 bp that contains the E-box bound by Mitf. Finally, we took advantage of a virus-based system to assess tissue specificity in vivo. To this end, a small fragment of the Oa1 promoter was cloned in front of a reporter gene in an adeno-associated virus. After we injected this virus into the subretinal space, we observed reporter gene expression specifically in the retinal pigment epithelium, confirming the cell-specific expression of the Oa1 promoter in the eye. The results obtained with this viral system are a preamble to the development of new gene delivery approaches for the treatment of retinal pigment epithelium defects.

This work was supported in part by research grant 1-FY01-117 from the March of Dimes Birth Defects Foundation, by research grants from Fondazione Telethon and the Vision of Children Foundation to V.M., by research grant 1R01EY015136-01 from NEI to A.B., and by grant AR43369 from NIAMS to D.E.F.

We thank J. Favor for Mitf mutant mice, R. Giavazzi for the B16-F10 melanoma cell line, C. Tacchetti and C. Valetti for the MNT-1 melanoma cell line, and G. Diez-Roux, M. Zollo, and A. D'Angelo for discussions of the data.