title: Transcription factor hierarchy in Waardenburg syndrome: regulation of MITF expression by SOX10 and PAX3.
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.
authors.affiliation: Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-4472, USA.
authors.forename: S B
authors.initials: SB
authors.lastname: Potterf
authors.forename: M
authors.initials: M
authors.lastname: Furumura
authors.forename: K J
authors.initials: KJ
authors.lastname: Dunn
authors.forename: H
authors.initials: H
authors.lastname: Arnheiter
authors.forename: W J
authors.initials: WJ
authors.lastname: Pavan
mesh_terms: D000818:Animals; D001483:Base Sequence; D017124:Conserved Sequence; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D019143:Evolution, Molecular; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D005838:Genotype; D006367:HeLa Cells; D006609:High Mobility Group Proteins / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D051739:Microphthalmia-Associated Transcription Factor; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009154:Mutation; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D010641:Phenotype; D011401:Promoter Regions, Genetic; D055757:SOXE Transcription Factors; D012689:Sequence Homology, Nucleic Acid; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics*; D014162:Transfection; D014849:Waardenburg Syndrome / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors; C527923:SOX10 protein, human; D055757:SOXE Transcription Factors; C527924:Sox10 protein, mouse; D014157:Transcription Factors; C068686:Pax3 protein, mouse