A big gene linked to small eyes encodes multiple Mitf isoforms: Many promoters make light work

Among more than 80 different loci related to mouse coat color, microphthalm ia-associated transcription factor (Mitf) encoded at the mouse microphthalm ia locus is one of the most exciting molecules that regulates the developme nt and survival of many cell types, including melanocyte, retinal pigment e pithelium (RPE), and mast cells. Mitf and its human homolog MITF consist of at least three isoforms, referred to as Mitf-A/MITF-A, the heart-type Mitf -H/MITF-H, and the melanocyte lineage-specific Mitf-M/MITF-M, respectively. These isoforms differ in the amino-terminal domains but share a transactiv ation domain and a basic helix-loop-helix and leucine-zipper structure that is required for DNA binding and dimerization. MITF-M is exclusively expres sed in melanocytes and melanoma cells, but not in other cell types, includi ng RPE cells. In contrast, MITF-A mRNA is widely expressed in many cell typ es. These three isoform mRNAs are possibly generated by differential usage of the gene promoters and by alternative splicing. We predict that the enti re MITF gene spans about 200 kb of DNA. Like MITF-M, MITF-A is able to acti vate the two melanogenesis gene promoters, tyrosinase and tyrosinase-relate d protein 1. These results suggest that melanogenesis may be regulated by d ifferent MITF isoforms in melanocyte and RPE. Possible implications of the multiplicity in Mitf/MITF isoforms are discussed.