Direct regulation of the Microphthalmia promoter by Sox10 links Waardenburg-Shah syndrome (WS4)-associated hypopigmentation and deafness to WS2.
The transcription factor Sox10 is genetically linked with Waardenburg syndrome 4 (WS4) in humans and the Dominant megacolon (Dom) mouse model for this disease. The pigmentary defects observed in the Dom mouse and WS4 are reminiscent of those associated with mutations in the microphthalmia (Mitf) gene, which encodes a transcription factor essential for the development of the melanocyte lineage. We demonstrate here that wild type Sox10 directly binds and activates transcription of the MITF promoter, whereas a mutant form of the Sox10 protein genetically linked with WS4 acts as a dominant-negative repressor of MITF expression and can reduce endogenous MITF protein levels. The ability of Sox10 to activate transcription of the MITF promoter implicates Sox10 in the regulation of melanocyte development and provides a molecular basis for the hypopigmentation and deafness associated with WS4.
Lee
M
M
Eukaryotic Transcription Laboratory, Marie Curie Research Institute, The Chart, Oxted, Surrey RH8 OTL, United Kingdom.
Goodall
J
J
Verastegui
C
C
Ballotti
R
R
Goding
C R
CR
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology*; D003638:Deafness / Q000235:genetics*; D005786:Gene Expression Regulation / Q000502:physiology*; D006609:High Mobility Group Proteins / Q000502:physiology*; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor; D010859:Pigmentation Disorders / Q000235:genetics*; D011401:Promoter Regions, Genetic; D055757:SOXE Transcription Factors; D014157:Transcription Factors; D014407:Tumor Cells, Cultured; D014849:Waardenburg Syndrome / Q000235:genetics*
D017931:DNA Primers; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; C527923:SOX10 protein, human; D055757:SOXE Transcription Factors; C527924:Sox10 protein, mouse; D014157:Transcription Factors