MOLECULAR GENETICS OF BHLH-ZIP TRANSCRIPTION FACTORS

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We are conducting studies to determine the function of the Mi-Tfe family of basic helix-loop-helix leucine zipper (bHLH-Zip) transcription factors in mammalian development. The Mi-Tfe family consists of four related genes- Mitf, Tfe3, Tfeb, and Tfec. The Mitf gene encodes the microphthalmia transcription factor (Mift). Mutations in the human MITF gene are responsible for a common human pigmentation and hearing disorder, Waardenburg syndrome type 2 (WS2). More than 20 independent Mitf mutations have been isolated in the mouse and shown to affect a number of cell types, including melanocytes, osteoclasts, and mast cells. In contrast, Tfeb, Tfe3, and Tfec were isolated by biochemical means and little is known about their function in vivo. In collaborative studies, we showed that the Mitf-Tfe proteins can bind the E-box sequence as homodimers or as heterodimers with other family members. To investigate the function of the Tfe genes in mammalian development, we used embryonic stem (ES) cell knockout technology to make germline null mutations in the three mouse Tfe genes. The effect of each mutation on development was then measured alone or in combination with mutations in other Mitf-Tfe family members. Surprisingly, these studies did not identify any essential functions for Mitf-Tfe heterodimers in development. This is in marked contrast to what has been observed for the Myc/Max/Mad family of bHLH-Zip proteins, where the heterodimers are thought to have essential functions. Future studies will attempt to use chemical mutagenesis and genetic modifier screens to identify other proteins in the Mitf signal transduction pathway.