Abstract
Genes associated with Hirschsprung disease, a failure to form enteric ganglia in the hindgut, were highly up-regulated in gut neural crest stem cells relative to whole-fetus RNA. One of these genes, the glial cell line-derived neurotrophic factor (GDNF) receptor Ret, was necessary for neural crest stem cell migration in the gut. GDNF promoted the migration of neural crest stem cells in culture but did not affect their survival or proliferation. Gene expression profiling, combined with reverse genetics and analyses of stem cell function, suggests that Hirschsprung disease is caused by defects in neural crest stem cell function.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cell Differentiation
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Cell Division
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Cell Movement
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Cell Separation
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Cell Survival
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Cells, Cultured
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Digestive System / cytology
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Digestive System / embryology*
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Digestive System / innervation
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Digestive System / metabolism
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Fetus / metabolism
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Gene Expression Profiling
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Gene Expression Regulation, Developmental*
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Glial Cell Line-Derived Neurotrophic Factor
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Glial Cell Line-Derived Neurotrophic Factor Receptors
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Hirschsprung Disease / etiology*
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Hirschsprung Disease / genetics
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Mice
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Multipotent Stem Cells / physiology*
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Nerve Growth Factors / genetics
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Nerve Growth Factors / metabolism
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Nerve Growth Factors / pharmacology
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Neural Crest / cytology*
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Neural Crest / physiology
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Oligonucleotide Array Sequence Analysis
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Proto-Oncogene Proteins / genetics*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-ret
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Rats
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Rats, Sprague-Dawley
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Receptor Protein-Tyrosine Kinases / genetics*
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Receptor Protein-Tyrosine Kinases / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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Up-Regulation
Substances
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Gdnf protein, mouse
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Gdnf protein, rat
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Glial Cell Line-Derived Neurotrophic Factor
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Glial Cell Line-Derived Neurotrophic Factor Receptors
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Nerve Growth Factors
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-ret
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Receptor Protein-Tyrosine Kinases
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Ret protein, mouse
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Ret protein, rat