Hirschsprung disease is linked to defects in neural crest stem cell function.
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.
Iwashita
Toshihide
T
Howard Hughes Medical Institute and Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109-0934, USA.
Kruger
Genevieve M
GM
Pardal
Ricardo
R
Kiel
Mark J
MJ
Morrison
Sean J
SJ
D000818:Animals; D002454:Cell Differentiation; D002455:Cell Division; D002465:Cell Movement; D002469:Cell Separation; D002470:Cell Survival; D002478:Cells, Cultured; D004064:Digestive System / Q000166:cytology / Q000196:embryology* / Q000294:innervation / Q000378:metabolism; D005333:Fetus / Q000378:metabolism; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D006627:Hirschsprung Disease / Q000209:etiology* / Q000235:genetics; D051379:Mice; D039902:Multipotent Stem Cells / Q000502:physiology*; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D009432:Neural Crest / Q000166:cytology* / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015854:Up-Regulation
C495040:Gdnf protein, mouse; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D009414:Nerve Growth Factors; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C494999:Ret protein, mouse; C495001:Ret protein, rat