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Identification of a melanocyte‐specific, microphthalmia‐associated transcription factor‐dependent regulatory element in the intronic duplication causing hair greying and melanoma in horses
Author(s) -
Sundström Elisabeth,
Komisarczuk Anna Z.,
Jiang Lin,
Golovko Anna,
Navratilova Pavla,
Rinkwitz Silke,
Becker Thomas S.,
Andersson Leif
Publication year - 2012
Publication title -
pigment cell and melanoma research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.618
H-Index - 105
eISSN - 1755-148X
pISSN - 1755-1471
DOI - 10.1111/j.1755-148x.2011.00902.x
Subject(s) - microphthalmia associated transcription factor , microphthalmia , melanocyte , biology , enhancer , transcription factor , zebrafish , gene duplication , genetics , neuroblastoma ras viral oncogene homolog , microbiology and biotechnology , gene , mutation , melanoma , kras
Summary Greying with age in horses is an autosomal dominant trait, characterized by hair greying, high incidence of melanoma and vitiligo‐like depigmentation. Previous studies have revealed that the causative mutation for this phenotype is a 4.6‐kb intronic duplication in STX17 (Syntaxin 17). By using reporter constructs in transgenic zebrafish, we show that a construct containing two copies of the duplicated sequence acts as a strong enhancer in neural crest cells and has subsequent melanophore‐specific activity during zebrafish embryonic development whereas a single copy of the duplicated sequence acts as a weak enhancer, consistent with the phenotypic manifestation of the mutation in horses. We further used luciferase assays to investigate regulatory regions in the duplication, to reveal tissue‐specific activities of these elements. One region upregulated the reporter gene expression in a melanocyte‐specific manner and contained two microphthalmia‐associated transcription factor (MITF) binding sites, essential for the activity. Microphthalmia‐associated transcription factor regulates melanocyte development, and these binding sites are outstanding candidates for mediating the melanocyte‐specific activity of the element. These results provide strong support for the causative nature of the duplication and constitute an explanation for the melanocyte‐specific effects of the Grey allele.