title: 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.
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), via P. Castellino 111, 80131 Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Vetrini
authors.forename: Alberto
authors.initials: A
authors.lastname: Auricchio
authors.forename: Jinyan
authors.initials: J
authors.lastname: Du
authors.forename: Barbara
authors.initials: B
authors.lastname: Angeletti
authors.forename: David E
authors.initials: DE
authors.lastname: Fisher
authors.forename: Andrea
authors.initials: A
authors.lastname: Ballabio
authors.forename: Valeria
authors.initials: V
authors.lastname: Marigo
mesh_terms: D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D000229:Dependovirus / Q000235:genetics; D005136:Eye Proteins / Q000096:biosynthesis* / Q000235:genetics*; D005347:Fibroblasts / Q000378:metabolism; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D008156:Luciferases / Q000378:metabolism; D008543:Melanins / Q000096:biosynthesis* / Q000378:metabolism; D020460:Melanosomes / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics*; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D041681:NIH 3T3 Cells; D010857:Pigment Epithelium of Eye / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012313:RNA / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012689:Sequence Homology, Nucleic Acid; D014018:Tissue Distribution; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D005136:Eye Proteins; C095276:GPR143 protein, human; D008543:Melanins; D008562:Membrane Glycoproteins; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; D014157:Transcription Factors; D012313:RNA; D008156:Luciferases