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.


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*


  • 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