Regulation of the microphthalmia-associated transcription factor gene by the Waardenburg syndrome type 4 gene, SOX10.
The absence of melanocytes from the cochlea and epidermis is responsible of deafness and hypopigmentation, two symptoms shared by the four Waardenburg syndrome (WS) subtypes. Microphthalmia-associated transcription factor (MITF) controls melanocyte survival and differentiation. Mutations, which impair MITF function or expression, result in an abnormal melanocyte development leading to the WS2. WS1 and WS3 are caused by mutation in the gene encoding the transcription factor Pax3, which regulates MITF expression. Recently, mutations in SOX10, a gene encoding a SRY-related transcription factor, have been reported in patients with WS4. However, the molecular basis of the defective melanocyte development in these patients remained to be elucidated. In the present report, we demonstrate that Sox10 is a strong activator of the MITF promoter, and we identify a Sox10 binding site between -264 and -266 of the MITF promoter. Finally, we show that three SOX10 mutations found in WS4 abolish the transcriptional activity of the resulting Sox10 proteins toward the MITF promoter. Taken together, our observations bring new and meaningful information concerning the molecular process that leads to a defective melanocyte development in WS4 patients with SOX10 mutations.
Verastegui
C
C
INSERM U385, Biologie et Physiopathologie de la Peau, Faculté de Médecine, Avenue de Valombrose, Nice, 06107 Cedex, France.
Bille
K
K
Ortonne
J P
JP
Ballotti
R
R
D016475:3T3 Cells; D000818:Animals; D015153:Blotting, Western; D003062:Codon; D018389:Codon, Nonsense; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D019334:Endothelin-3 / Q000235:genetics; D004843:Epistasis, Genetic; D016368:Frameshift Mutation; D017353:Gene Deletion; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006609:High Mobility Group Proteins / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D051821:Lymphoid Enhancer-Binding Factor 1; D008544:Melanocytes / Q000378:metabolism; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor; D009154:Mutation; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D055757:SOXE Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D014849:Waardenburg Syndrome / Q000235:genetics*
D003062:Codon; D018389:Codon, Nonsense; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D019334:Endothelin-3; D006609:High Mobility Group Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; 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; D008156:Luciferases