title: Disturbances of colonic motility in mouse models of Hirschsprung's disease.
abstract: Mutations in genes encoding members of the GDNF and endothelin-3 (Et-3) signaling pathways can cause Hirschsprung's disease, a congenital condition associated with an absence of enteric neurons in the distal gut. GDNF signals through Ret, a receptor tyrosine kinase, and Et-3 signals through endothelin receptor B (Ednrb). The effects of Gdnf, Ret, and ET-3 haploinsufficiency and a null mutation in ET-3 on spontaneous motility patterns in adult and developing mice were investigated. Video recordings were used to construct spatiotemporal maps of spontaneous contractile patterns in colon from postnatal and adult mice in vitro. In Ret(+/-) and ET-3(+/-) mice, which have normal numbers of enteric neurons, colonic migrating motor complexes (CMMCs) displayed similar properties under control conditions and following inhibition of nitric oxide synthase (NOS) activity to wild-type mice. In the colon of Gdnf(+/-) mice and in the ganglionic region of ET-3(-/-) mice, there was a 50-60% reduction in myenteric neuron number. In Gdnf(+/-) mice, CMMCs were present, but abnormal, and the proportion of myenteric neurons containing NOS was not different from that of wild-type mice. In the ganglionic region of postnatal ET-3(-/-) mice, CMMCs were absent, and the proportion of myenteric neurons containing NOS was over 100% higher than in wild-type mice. Thus impairments in spontaneous motility patterns in the colon of Gdnf(+/-) mice and in the ganglionic region of ET-3(-/-) mice are correlated with a reduction in myenteric neuron density.
authors.affiliation: Dept. of Physiology, Univ. of Melbourne, Parkville, Vic 3010, Australia. r.roberts1@pgrad.unimelb.edu.au
authors.forename: Rachael R
authors.initials: RR
authors.lastname: Roberts
authors.forename: Joel C
authors.initials: JC
authors.lastname: Bornstein
authors.forename: Annette J
authors.initials: AJ
authors.lastname: Bergner
authors.forename: Heather M
authors.initials: HM
authors.lastname: Young
mesh_terms: D000367:Age Factors; D000375:Aging / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D003106:Colon / Q000187:drug effects / Q000294:innervation / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D019334:Endothelin-3 / Q000235:genetics / Q000378:metabolism*; D017615:Enteric Nervous System / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005769:Gastrointestinal Motility / Q000187:drug effects; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D017829:Granisetron / Q000494:pharmacology; D006627:Hirschsprung Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016065:Myoelectric Complex, Migrating; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D019335:Nitroarginine / Q000494:pharmacology; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism*; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism; D058831:Serotonin 5-HT3 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D013997:Time Factors; D014741:Video Recording
chemical_list: D019334:Endothelin-3; D004791:Enzyme Inhibitors; D051100:Glial Cell Line-Derived Neurotrophic Factor; D017829:Granisetron; D019001:Nitric Oxide Synthase; D019335:Nitroarginine; D051096:Proto-Oncogene Proteins c-ret; D044406:Receptors, Serotonin, 5-HT3; D058831:Serotonin 5-HT3 Receptor Antagonists; D012702:Serotonin Antagonists; C495040:Gdnf protein, mouse; C494999:Ret protein, mouse