The timing and location of glial cell line-derived neurotrophic factor expression determine enteric nervous system structure and function.
Ret signaling is critical for formation of the enteric nervous system (ENS) because Ret activation promotes ENS precursor survival, proliferation, and migration and provides trophic support for mature enteric neurons. Although these roles are well established, we now provide evidence that increasing levels of the Ret ligand glial cell line-derived neurotrophic factor (GDNF) in mice causes alterations in ENS structure and function that are critically dependent on the time and location of increased GDNF availability. This is demonstrated using two different strains of transgenic mice and by injecting newborn mice with GDNF. Furthermore, because different subclasses of ENS precursors withdraw from the cell cycle at different times during development, increases in GDNF at specific times alter the ratio of neuronal subclasses in the mature ENS. In addition, we confirm that esophageal neurons are GDNF responsive and demonstrate that the location of GDNF production influences neuronal process projection for NADPH diaphorase-expressing, but not acetylcholinesterase-, choline acetyltransferase-, or tryptophan hydroxylase-expressing, small bowel myenteric neurons. We further demonstrate that changes in GDNF availability influence intestinal function in vitro and in vivo. Thus, changes in GDNF expression can create a wide variety of alterations in ENS structure and function and may in part contribute to human motility disorders.
Wang
Hongtao
H
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Hughes
Inna
I
Planer
William
W
Parsadanian
Alexander
A
Grider
John R
JR
Vohra
Bhupinder P S
BP
Keller-Peck
Cynthia
C
Heuckeroth
Robert O
RO
D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation; D017615:Enteric Nervous System / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D004947:Esophagus / Q000196:embryology / Q000294:innervation; D005769:Gastrointestinal Motility / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009197:Myenteric Plexus / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D009252:NADPH Dehydrogenase / Q000378:metabolism; D016501:Neurites / Q000378:metabolism / Q000648:ultrastructure; D055495:Neurogenesis / Q000187:drug effects / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
D051100:Glial Cell Line-Derived Neurotrophic Factor; D009252:NADPH Dehydrogenase; D051096:Proto-Oncogene Proteins c-ret