Transcription factor hierarchy in Waardenburg syndrome: regulation of MITF expression by SOX10 and PAX3

S B Potterf; M Furumura; K J Dunn; H Arnheiter; W J Pavan

doi:10.1007/s004390000328

Transcription factor hierarchy in Waardenburg syndrome: regulation of MITF expression by SOX10 and PAX3

Hum Genet. 2000 Jul;107(1):1-6. doi: 10.1007/s004390000328.

Authors

S B Potterf¹, M Furumura, K J Dunn, H Arnheiter, W J Pavan

Affiliation

¹ Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-4472, USA.

PMID: 10982026
DOI: 10.1007/s004390000328

Abstract

Waardenburg syndrome (WS) is associated with neural crest-derived melanocyte deficiency caused by mutations in either one of three transcription factors: MITF, PAX3, and SOX10. However, the hierarchical relationship of these transcription factors is largely unknown. We show that SOX10 is capable of transactivating the MITF promoter 100-fold, and that this transactivation is further stimulated by PAX3. Promoter deletion and mutational analyses indicate that SOX10 can activate MITF expression through binding to a region that is evolutionarily conserved between the mouse and human MITF promoters. A SOX10 mutant that models C-terminal truncations in WS can reduce wild-type SOX10 induction of MITF, suggesting these mutations may act in a dominant-negative fashion. Our data support a model in which the hypopigmentation in WS, of which these factors have been implicated, results from a disruption in function of the central melanocyte transcription factor MITF.

MeSH terms

Animals
Base Sequence
Conserved Sequence
DNA-Binding Proteins / biosynthesis
DNA-Binding Proteins / genetics*
Evolution, Molecular
Gene Deletion
Gene Expression Regulation*
Genes, Dominant
Genotype
HeLa Cells
High Mobility Group Proteins / biosynthesis
High Mobility Group Proteins / genetics*
Humans
Mice
Mice, Inbred C3H
Mice, Inbred C57BL
Mice, Mutant Strains
Microphthalmia-Associated Transcription Factor
Molecular Sequence Data
Mutagenesis
Mutation
PAX3 Transcription Factor
Paired Box Transcription Factors
Phenotype
Promoter Regions, Genetic
SOXE Transcription Factors
Sequence Homology, Nucleic Acid
Time Factors
Transcription Factors / genetics*
Transfection
Waardenburg Syndrome / genetics*

Substances

DNA-Binding Proteins
High Mobility Group Proteins
MITF protein, human
Microphthalmia-Associated Transcription Factor
Mitf protein, mouse
PAX3 Transcription Factor
PAX3 protein, human
Paired Box Transcription Factors
SOX10 protein, human
SOXE Transcription Factors
Sox10 protein, mouse
Transcription Factors
Pax3 protein, mouse