microphthalmia, a critical factor in melanocyte development, defines a discrete transcription factor family
Open accessAbstract
The microphthalmia (mi) gene appears essential for pigment cell development and/or survival, based on its mutation in mi mice. It has also been 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 that Mi protein binds DNA as a homo- or heterodimer with TFEB, TFE3, or TFEC, together constituting a new MiT family. Mi can also activate transcription through recognition of the M box, a highly conserved pigmentation gene promoter element, and may thereby determine tissue-specific 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 spliced exon located outside of the b-HLH-ZIP region is shown to significantly modulate DNA recognition by the basic domain. These findings suggest that Mi's critical roles in melanocyte survival and pigmentation are mediated by MiT family interactions and transcriptional activities.
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Mitfa and Tfec have the potential to physically interact as a heterodimer.
“Notably, Mitfa and Tfec have the potential to physically interact as a heterodimer [57, 58], which adds an additional layer of complexity when attempting to elucidate the mechanism of cell fate choice.”
From The MITF paralog tfec is required in neural crest development for fate specification of the iridophore lineage from a multipotent pigment cell progenitor (2021) · cites this paper as [57]
The ‘Mi is a member of a discrete family of b-HLH-ZIP factors’ section reports that Mi and TFEC form stable DNA-binding heterodimers, supporting the potential for this type of interaction. The paper tests Mi and TFEC in vitro, however, rather than directly testing the specifically named Mitfa and Tfec proteins. (LLM, conf=0.82)
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- Authors
- Hemesath, T. J., Steingrímsson, E., McGill, G., Hansen, M. J., Vaught, J., Hodgkinson, C. A., Arnheiter, H., Copeland, N. G., Jenkins, N. A., & Fisher, D. E.
- Affiliations
- Dana-Farber Cancer Institute (US)
- Harvard University (US)
- National Institutes of Health (US)
- Houston Methodist (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 1994-11-15
- Volume
- 8
- Issue
- 22
- Pages
- 2770-2780
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- OpenAlex
- W2125842849
- Cited by
- 673
- References
- 1
- Citations by year
- 2026: 11 · 2025: 9 · 2024: 23 · 2023: 41 · 2022: 25 · 2021: 31 · 2020: 31 · 2019: 18 · 2018: 21 · 2017: 23 · 2016: 22 · 2015: 14 · 2014: 18 · 2013: 18 · 2012: 20
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (n01co074101-034)
- National Cancer Institute (N01 CO-74101)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › melanin and skin pigmentation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- melanocyte development, melanocyte survival, pigmentation, Waardenburg syndrome, bHLH-Zip transcription factors, TFEB, TFE3, TFEC, transcriptional activation, alternative splicing, DNA binding, protein dimerization
- MeSH terms
- Animals, Base Sequence, DNA-Binding Proteins, Gene Expression Regulation, Melanocytes, Molecular Sequence Data, Mutation, Transcription Factors, Alternative Splicing, Genes, Reporter, Mice, Microphthalmia-Associated Transcription Factor
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