title: Essential roles of enteric neuronal serotonin in gastrointestinal motility and the development/survival of enteric dopaminergic neurons.
abstract: The gut contains a large 5-HT pool in enterochromaffin (EC) cells and a smaller 5-HT pool in the enteric nervous system (ENS). During development, enteric neurons are generated asynchronously. We tested hypotheses that serotonergic neurons, which arise early, affect development/survival of later-born dopaminergic, GABAergic, nitrergic, and calcitonin gene-related peptide-expressing neurons and are essential for gastrointestinal motility. 5-HT biosynthesis depends on tryptophan hydroxylase 1 (TPH1) in EC cells and on TPH2 in neurons; therefore, mice lacking TPH1 and/or TPH2 distinguish EC-derived from neuronal 5-HT. Deletion of TPH2, but not TPH1, decreased myenteric neuronal density and proportions of dopaminergic and GABAergic neurons but did not affect the extrinsic sympathetic innervation of the gut; intestinal transit slowed in mice lacking TPH2 mice, but gastric emptying accelerated. Isolated enteric crest-derived cells (ENCDCs) expressed the serotonin reuptake transporter (SERT) and 15 subtypes of 5-HT receptor. Addition of 5-HT to cultures of isolated ENCDCs promoted total and dopaminergic neuronal development. Rings of SERT-immunoreactive terminal axons surrounded myenteric dopaminergic neurons and SERT knock-out increased intestinal levels of dopamine metabolites, implying that enteric dopaminergic neurons receive a serotonergic innervation. Observations suggest that constitutive gastrointestinal motility depends more on neuronal than EC cell serotonin; moreover, serotonergic neurons promote development/survival of some classes of late-born enteric neurons, including dopaminergic neurons, which appear to innervate and activate in the adult ENS.
authors.affiliation: Department of Pathology, Columbia University, New York, New York 10032, USA. zl64@columbia.edu
authors.forename: Zhishan
authors.initials: Z
authors.lastname: Li
authors.forename: Alcmène
authors.initials: A
authors.lastname: Chalazonitis
authors.forename: Yung-Yu
authors.initials: YY
authors.lastname: Huang
authors.forename: J John
authors.initials: JJ
authors.lastname: Mann
authors.forename: Kara Gross
authors.initials: KG
authors.lastname: Margolis
authors.forename: Qi Melissa
authors.initials: QM
authors.lastname: Yang
authors.forename: Dolly O
authors.initials: DO
authors.lastname: Kim
authors.forename: Francine
authors.initials: F
authors.lastname: Côté
authors.forename: Jacques
authors.initials: J
authors.lastname: Mallet
authors.forename: Michael D
authors.initials: MD
authors.lastname: Gershon
mesh_terms: D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D051959:ELAV Proteins / Q000378:metabolism; D000067778:ELAV-Like Protein 3; D004622:Embryo, Mammalian; D017615:Enteric Nervous System / Q000166:cytology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005746:Gastric Emptying / Q000187:drug effects / Q000235:genetics; D005769:Gastrointestinal Motility / Q000187:drug effects / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006719:Homovanillic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D066298:In Vitro Techniques; D007421:Intestine, Small / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009197:Myenteric Plexus / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism* / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000172:deficiency / Q000378:metabolism; D014365:Tryptophan Hydroxylase / Q000172:deficiency; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D051959:ELAV Proteins; D000067778:ELAV-Like Protein 3; C490263:Elavl3 protein, mouse; D004791:Enzyme Inhibitors; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; C003753:vanillactic acid; D012701:Serotonin; D005680:gamma-Aminobutyric Acid; D052248:Nitric Oxide Synthase Type I; D014446:Tyrosine 3-Monooxygenase; C487801:Tph1 protein, mouse; C487802:Tph2 protein, mouse; D014365:Tryptophan Hydroxylase; D015740:Calcitonin Gene-Related Peptide; D004298:Dopamine; D006719:Homovanillic Acid