Identification of a melanocyte-specific, microphthalmia-associated transcription factor-dependent regulatory element in the intronic duplication causing hair greying and melanoma in horses
2012 (English)In: Pigment Cell & Melanoma Research, ISSN 1755-1471, Vol. 25, no 1, 28-36 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2012. Vol. 25, no 1, 28-36 p.
melanoma, hair greying, horses, zebrafish, STX17, NR4A3, microphthalmia-associated transcription factor
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-168743DOI: 10.1111/j.1755-148X.2011.00902.xISI: 000298577600007OAI: oai:DiVA.org:uu-168743DiVA: diva2:503690