Pax3 is required for enteric ganglia formation and functions with Sox10 to modulate expression of c-ret.
Hirschsprung disease and Waardenburg syndrome are human genetic diseases characterized by distinct neural crest defects. Patients with Hirschsprung disease suffer from gastrointestinal motility disorders, whereas Waardenburg syndrome consists of defective melanocyte function, deafness, and craniofacial abnormalities. Mutations responsible for Hirschsprung disease and Waardenburg syndrome have been identified, and some patients have been described with characteristics of both disorders. Here, we demonstrate that PAX3, which is often mutated in Waardenburg syndrome, is required for normal enteric ganglia formation. Pax3 can bind to and activate expression of the c-RET gene, which is often mutated in Hirschsprung disease. Pax3 functions with Sox10 to activate transcription of c-RET, and SOX10 mutations result in Waardenburg-Hirschsprung syndrome. Thus, Pax3, Sox10, and c-Ret are components of a neural crest development pathway, and interruption of this pathway at various stages results in neural crest-related human genetic syndromes.
Lang
D
D
Cardiovascular Division, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Chen
F
F
Milewski
R
R
Li
J
J
Lu
M M
MM
Epstein
J A
JA
D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics*; D029721:Drosophila Proteins; D017615:Enteric Nervous System / Q000196:embryology*; D005724:Ganglia / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D006609:High Mobility Group Proteins / Q000235:genetics*; D006627:Hirschsprung Disease / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009432:Neural Crest / Q000196:embryology*; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis*; D055757:SOXE Transcription Factors; D014157:Transcription Factors; D014849:Waardenburg Syndrome / Q000235:genetics
D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D006609:High Mobility Group Proteins; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors; D011518:Proto-Oncogene Proteins; C527923:SOX10 protein, human; D055757:SOXE Transcription Factors; C527924:Sox10 protein, mouse; D014157:Transcription Factors; C068686:Pax3 protein, mouse; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; C494999:Ret protein, mouse