Melanocyte development in vivo and in neural crest cell cultures: crucial dependence on the Mitf basic-helix-loop-helix-zipper transcription factor.
The more than 20 different Mitf mutations in the mouse are all associated with deficiencies in neural crest-derived melanocytes that range from minor functional disturbances with some alleles to complete absence of mature melanocytes with others. In the trunk region of wild-type embryos, Mitf-expressing cells that coexpressed the melanoblast marker Dct and the tyrosine kinase receptor Kit were found in the dorsolateral neural crest migration pathway. In contrast, in embryos homozygous for an Mitf allele encoding a non-functional Mitf protein, Mitf-expressing cells were extremely rare, no Dct expression was ever found, and the number of Kit-expressing cells was much reduced. Wild-type neural crest cell cultures rapidly gave rise to cells that expressed Mitf and coexpressed Kit and Dct. With time in culture, Kit expression was increased, and pigmented, dendritic cells developed. Addition of the Kit ligand Mgf or endothelin 3 or a combination of these factors all rapidly increased the number of Dct-positive cells. Cultures from Mitf mutant embryos initially displayed Mitf-positive cells similar in numbers and Kit-expression as did wild-type cultures. However, Kit expression did not increase with time in culture and the mutant cells never responded to Mgf or endothelin 3, did not express Dct, and never showed pigment. In fact, even Mitf expression was rapidly lost. The results suggest that Mitf first plays a role in promoting the transition of precursor cells to melanoblasts and subsequently, by influencing Kit expression, melanoblast survival.
Opdecamp
K
K
Laboratory of Developmental Neurogenetics, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
Nakayama
A
A
Nguyen
M T
MT
Hodgkinson
C A
CA
Pavan
W J
WJ
Arnheiter
H
H
D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000502:physiology*; D004622:Embryo, Mammalian / Q000502:physiology; D019334:Endothelin-3 / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental; D019746:Intramolecular Oxidoreductases; D007535:Isomerases / Q000235:genetics; D008544:Melanocytes / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D051739:Microphthalmia-Associated Transcription Factor; D008969:Molecular Sequence Data; D009154:Mutation; D009432:Neural Crest / Q000166:cytology* / Q000196:embryology*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D019089:Stem Cell Factor / Q000494:pharmacology; D014157:Transcription Factors
D004268:DNA-Binding Proteins; D019334:Endothelin-3; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; D019089:Stem Cell Factor; D014157:Transcription Factors; D019009:Proto-Oncogene Proteins c-kit; D007535:Isomerases; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase