PUBLICATION
Identification of a melanocyte-specific, microphthalmia-associated transcription factor-dependent regulatory element in the intronic duplication causing hair greying and melanoma in horses
- Authors
- Sundström, E., Komisarczuk, A.Z., Jiang, L., Golovko, A., Navratilova, P., Rinkwitz, S., Becker, T.S., and Andersson, L.
- ID
- ZDB-PUB-110907-17
- Date
- 2012
- Source
- Pigment cell & melanoma research 25(1): 28-36 (Journal)
- Registered Authors
- Becker, Thomas S., Navratilova, Pavla, Rinkwitz, Silke
- Keywords
- melanoma, hair greying, horses, zebrafish, STX17, NR4A3, MITF
- MeSH Terms
-
- Aging/genetics
- Animals
- Animals, Genetically Modified
- Binding Sites
- Enhancer Elements, Genetic*
- Gene Dosage
- Gene Duplication*
- Gene Expression Regulation, Developmental
- Genes, Dominant
- Genes, Reporter
- Hair Color/genetics*
- Horse Diseases/genetics*
- Horses/genetics*
- Humans
- Introns/genetics*
- Mammals
- Melanocytes/metabolism*
- Melanoma/genetics
- Melanoma/veterinary*
- Melanophores/metabolism
- Microphthalmia-Associated Transcription Factor/metabolism*
- Neural Crest/cytology
- Phenotype
- Qa-SNARE Proteins/genetics*
- Qa-SNARE Proteins/physiology
- Skin Neoplasms/genetics
- Skin Neoplasms/veterinary*
- Species Specificity
- Zebrafish
- PubMed
- 21883983 Full text @ Pigment Cell Melanoma Res.
Citation
Sundström, E., Komisarczuk, A.Z., Jiang, L., Golovko, A., Navratilova, P., Rinkwitz, S., Becker, T.S., and Andersson, L. (2012) Identification of a melanocyte-specific, microphthalmia-associated transcription factor-dependent regulatory element in the intronic duplication causing hair greying and melanoma in horses. Pigment cell & melanoma research. 25(1):28-36.
Abstract
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 MITF (microphthalmia-associated transcription factor) binding sites, essential for the activity. MITF 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping