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PMID: 11032856 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Pax3 is required for enteric ganglia formation and functions with Sox10 to modulate expression of c-ret.

The Journal of clinical investigation ·Vol. 106 ·No. 8 ·2000-10-00 ·Pages 963-71

Lang D, Chen F, Milewski R, Li J, Lu MM, Epstein JA

Abstract

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.

MeSH Terms
Animals DNA-Binding Proteins/genetics Drosophila Proteins Enteric Nervous System/embryology Ganglia/metabolism Gene Expression Regulation, Developmental High Mobility Group Proteins/genetics Hirschsprung Disease/genetics Humans Mice Mice, Transgenic Neural Crest/embryology PAX3 Transcription Factor Paired Box Transcription Factors Proto-Oncogene Proteins/biosynthesis Proto-Oncogene Proteins c-ret Receptor Protein-Tyrosine Kinases/biosynthesis SOXE Transcription Factors Transcription Factors Waardenburg Syndrome/genetics
Chemicals
DNA-Binding Proteins Drosophila Proteins High Mobility Group Proteins PAX3 Transcription Factor PAX3 protein, human Paired Box Transcription Factors Proto-Oncogene Proteins SOX10 protein, human SOXE Transcription Factors Sox10 protein, mouse Transcription Factors Pax3 protein, mouse Proto-Oncogene Proteins c-ret Receptor Protein-Tyrosine Kinases Ret protein, Drosophila Ret protein, mouse
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Lang D
Cardiovascular Division, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Chen F
Milewski R
Li J
Lu M M
Epstein J A
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI10828
Published
2000-10-00
Pages
963-71
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC314346
Subset
IM
Grants
NHLBI NIH HHS · R01HL62974 · United States
NIDDK NIH HHS · R01DK57050 · United States
NIDDK NIH HHS · P30 DK050306 · United States
NHLBI NIH HHS · R01 HL061475 · United States
NHLBI NIH HHS · R01HL61475 · United States
NHLBI NIH HHS · R01 HL062974 · United States
External Links
PubMed source DOI: 10.1172/JCI10828 PMC Full Text View journal details
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