mitfa is required at multiple stages of melanocyte differentiation but not to establish the melanocyte stem cell
Open accessAbstract
The mitfa gene encodes a zebrafish ortholog of the microphthalmia-associated transcription factor (Mitf) which, like its counterparts in other species, is absolutely required for development of neural crest melanocytes. In order to evaluate mitfa's role in different stages of melanocyte development, we have identified hypomorphic alleles of mitfa, including two alleles that are temperature-sensitive for melanocyte development. Molecular analysis revealed that the mitf(fh53)ts results from a single base pair change producing an asparagine to tyrosine amino acid substitution in the DNA-binding domain, and the mitfa(vc7)ts allele is a mutation in a splice donor site that reduces the level of correctly-spliced transcripts. Splicing in the mitfa(vc7) allele does not itself appear to be temperature-dependent. A third, hypomorphic allele, mitfa(z25) results in an isoleucine to phenylalanine substitution in the first helix domain of the protein. Temperature upshift experiments with mitfa(fh53)ts show that mitfa is required at several stages of melanocyte differentiation, including for expression of the early melanoblast marker dct, again for progression from dct expression to differentiation, and again for maintenance of dendritic form following differentiation. mitfa(fh53)ts mutants recover melanocytes within 2-3days when downshifted at all stages of larval development. However, when melanocyte stem cells (MSCs) are ablated by early treatment with the erbB3 inhibitor AG1478, melanocyte recovery is lost by 48 h. This result indicates first that the MSC is established at the restrictive temperature, and that melanoblasts die or lose the ability to recover after being held at the restrictive temperature for approximately one day.
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Following development at 25°C, melanocyte numbers, morphology, and pigmentation in mitfavc7 are indistinguishable from wild-type zebrafish.
“We note the possibility that mitfa may be partially compromised by aberrant splicing products in this mutant at permissive temperatures, but following development at 25°C, melanocyte numbers, morphology, and pigmentation are indistinguishable from wild-type zebrafish [41].”
From Gene Expression Analysis of Zebrafish Melanocytes, Iridophores, and Retinal Pigmented Epithelium Reveals Indicators of Biological Function and Developmental Origin (2013) · cites this paper as [41]
The Results section, “Identification of temperature-sensitive alleles of mitfa” (page unavailable), says mitfavc7 developed a normal or nearly normal melanocyte pattern at 25°C. It also says the allele appeared somewhat compromised even at 23°C. The source therefore supports a near-normal pattern at 25°C, but not the stronger claim that melanocyte numbers, morphology, and pigmentation were all indistinguishable from wild type. (LLM, conf=0.88)
Experimental — accuracy not yet measuredMelanocytes, iridophores, and RPE develop normally at 25°C in mitfavc7.
“Melanocytes, iridophores, and RPE develop normally at 25°C in mitfavc7.”
From Gene Expression Analysis of Zebrafish Melanocytes, Iridophores, and Retinal Pigmented Epithelium Reveals Indicators of Biological Function and Developmental Origin (2013) · cites this paper as [41]
The Results section (‘Identification of temperature-sensitive alleles of mitfa’; page unavailable) says mitfavc7 develops normal or nearly normal melanocyte patterns at 25°C, not unequivocally normal ones. The paper also says RPE has no requirement for mitfa, but it does not establish that iridophores develop normally in mitfavc7 at 25°C; its discussion of excess iridophores concerns temperature-sensitive alleles at restrictive temperatures. (LLM, conf=0.85)
Experimental — accuracy not yet measuredmitfa is not required for RPE development in zebrafish.
“This mutant facilitated the collection of RPE, as mitfa is not required for RPE development in zebrafish [41].”
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- Authors
- Johnson, S. L., Nguyen, A. N., & Lister, J. A.
- Affiliations
- Washington University in St. Louis (US)
- Virginia Commonwealth University (US)
- Corresponding author
- Lister, James A.
- ORCID
- Johnson, Stephen L.
- Venue
- Developmental Biology
- Publisher
- Elsevier BV
- Published
- 2011-02
- Volume
- 350
- Issue
- 2
- Pages
- 405-413
- ISSN
- 0012-1606 (ISSN-L)
- PMC
- PMC3040983
- OpenAlex
- W2024114735
- Cited by
- 85
- References
- 0
- Citations by year
- 2026: 6 · 2025: 2 · 2024: 6 · 2023: 1 · 2022: 10 · 2021: 6 · 2020: 7 · 2019: 10 · 2018: 3 · 2017: 4 · 2016: 5 · 2015: 4 · 2014: 5 · 2013: 8 · 2012: 4
- FWCI
- 2.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Developmental Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Cancer Society (IRG-99-225-04)
- Concern Foundation
- NIH (RO1-GM56988)
- 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 › Cell Biology › Zebrafish Biomedical Research Applications
- Keywords
- mitfa, MITF, melanocyte differentiation, melanocyte stem cells, zebrafish, temperature-sensitive allele, hypomorphic mutation, discrete cosine transform, dendritic melanocytes, AG1478
- MeSH terms
- Animals, Cell Differentiation, Melanocytes, Stem Cells, Temperature, Zebrafish, Zebrafish Proteins, Microphthalmia-Associated Transcription Factor
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