Disease relevance of mitfa

• To directly test the role of activated BRAF in nevus and melanoma development, we have generated transgenic zebrafish expressing the most common BRAF mutant form (V600E) under the control of the melanocyte mitfa promoter [1].
• This promoter binds to zebrafish Lef1 protein in vitro, and a nacre reporter construct is strongly repressed by dominant-negative Tcf in melanoma cells [2].

High impact information on mitfa

• We generated phenocopies of mutations of the genes no tail (ref. 2), chordin (ref. 3), one-eyed-pinhead (ref. 4), nacre (ref. 5) and sparse (ref. 6), removing gene function from maternal through post-segmentation and organogenesis developmental stages [3].
• We have shown that Wnt signals are necessary and sufficient for neural crest cells to adopt pigment cell fates. nacre, a zebrafish homolog of MITF, is required for pigment cell differentiation [2].
• We isolated a promoter region of nacre that contains Tcf/Lef binding sites, which can mediate Wnt responsiveness [2].
• Wnt signaling therefore directly activates nacre, which in turn leads to pigment cell differentiation [2].
• Transcription factors mitfa and mitfb, results of a teleost-specific duplication, partition gene expression and function between different sets of melanocytes [4].

Biological context of mitfa

• We demonstrate that the zebrafish mitfa promoter has sox10 binding sites necessary for activity in vitro, consistent with studies using mammalian cell cultures that have shown that Sox10 directly regulates Mitf expression [5].

Anatomical context of mitfa

• Mutations in the zebrafish nacre/mitfa gene, expressed in all embryonic melanogenic cells, perturb only neural crest melanocytes, suggesting redundancy of mitfa with another gene in the zebrafish retinal pigment epithelium (RPE) [6].
• Analysis of expression of dopachrome tautomerase (dct) and microphthalmia (mitfa) suggests that melanophore precursors are specified normally in homozygous tct mutants [7].

Other interactions of mitfa

• By transplanting cells between fms mutants and either wild-type or nacre mutant zebrafish, we show that fms acts autonomously to the xanthophore lineage in promoting the striped arrangement of adult melanophores [8].

References