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	S B Potterf, M Furumura, K J Dunn, H Arnheiter, W J Pavan
Journal	Human genetics (Hum Genet) Vol. 107 Issue 1 Pg. 1-6 (Jul 2000) ISSN: 0340-6717 [Print] Germany
PMID	10982026 (Publication Type: Journal Article)
Chemical References	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
Topics	Animals Base Sequence Conserved Sequence DNA-Binding Proteins (biosynthesis, genetics) Evolution, Molecular Gene Deletion Gene Expression Regulation Genes, Dominant Genotype HeLa Cells High Mobility Group Proteins (biosynthesis, 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)

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