MICROPHTHALMIA, A CRITICAL FACTOR IN MELANOCYTE DEVELOPMENT, DEFINES A DISCRETE TRANSCRIPTION FACTOR FAMILY

The microphthalmia (mi) gene appears essential for pigment cell develo pment and/or survival, based on its mutation in mi mice, It has also b een linked to the human disorder Waardenburg Syndrome. The mi gene was recently cloned and predicts a basic/helix-loop-helix/leucine zipper (b-HLH-ZIP) factor with tissue-restricted expression. Here, we show th at Mi protein binds DNA as a homo- or heterodimer with TEEB, TEE3, or TFEC, together constituting a new MiT family. Mi can also activate tra nscription through recognition of the M box, a highly conserved pigmen tation gene promoter element, and may thereby determine tissue specifi c expression of pigmentation enzymes. Six mi mutations shown recently to cluster in the b-HLH-ZIP region produce surprising and instructive effects on DNA recognition and oligomerization. An alternatively splic ed exon located outside of the b-HLH-ZIP region is shown to significan tly modulate DNA recognition by the basic domain. These findings sugge st that Mi's critical roles in melanocyte survival and pigmentation ar e mediated by MiT family interactions and transcriptional activities.