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.