title: Genetic evidence does not support direct regulation of EDNRB by SOX10 in migratory neural crest and the melanocyte lineage.
abstract: Mutations in the transcription factor Sox10 or Endothelin Receptor B (Ednrb) result in Waardenburg Syndrome Type IV (WS-IV), which presents with deficiencies of neural crest derived melanocytes (hypopigmentation) and enteric ganglia (hypoganglionosis). As Sox10 and Ednrb are expressed in mouse migratory neural crest cells and melanoblasts, we investigated the possibility that SOX10 and EDNRB function through a hierarchical relationship during melanocyte development. However, our results support a distinct rather than hierarchical relationship. First, SOX10 expression continues in Ednrb null melanoblasts, demonstrating that SOX10 expression is not dependent on EDNRB function. Second, Ednrb expression persists in E10.5 Sox10null embryos, demonstrating that Ednrb is not dependent on SOX10 for expression in migratory neural crest cells. Third, over-expression of SOX10 in melanoblasts of mice that harbor null or hypomorphic Ednrb alleles does not rescue hypopigmentation, suggesting that SOX10 overexpression can neither complement a lack of EDNRB function nor increase Ednrb expression. Fourth, mice that are double heterozygous for loss-of-function mutations in Sox10 and Ednrb do not demonstrate synergistically increased hypopigmentation compared to mice that are single heterozygotes for either mutation alone, suggesting a lack of direct genetic interaction between these genes. Our results suggest that SOX10 does not directly activate Ednrb transcription in the melanocyte lineage. Given that SOX10 directly activates Ednrb in the enteric nervous system, our results suggest that SOX10 may differentially activate target genes based on the particular cellular context.
authors.affiliation: Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-4472, USA.
authors.forename: Ramin Mollaaghababa
authors.initials: RM
authors.lastname: Hakami
authors.forename: Ling
authors.initials: L
authors.lastname: Hou
authors.forename: Laura L
authors.initials: LL
authors.lastname: Baxter
authors.forename: Stacie K
authors.initials: SK
authors.lastname: Loftus
authors.forename: E Michelle
authors.initials: EM
authors.lastname: Southard-Smith
authors.forename: Arturo
authors.initials: A
authors.lastname: Incao
authors.forename: Jun
authors.initials: J
authors.lastname: Cheng
authors.forename: William J
authors.initials: WJ
authors.lastname: Pavan
mesh_terms: D000818:Animals; D019070:Cell Lineage / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D006579:Heterozygote; D006609:High Mobility Group Proteins / Q000235:genetics / Q000378:metabolism*; D017496:Hypopigmentation / Q000235:genetics / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000235:genetics; D008544:Melanocytes / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009432:Neural Crest / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D044023:Receptor, Endothelin B / Q000235:genetics / Q000378:metabolism*; D055757:SOXE Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D006609:High Mobility Group Proteins; D009363:Neoplasm Proteins; D044023:Receptor, Endothelin B; D055757:SOXE Transcription Factors; C527924:Sox10 protein, mouse; D014157:Transcription Factors; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase