5-HT4 receptor-mediated neuroprotection and neurogenesis in the enteric nervous system of adult mice.
Although the mature enteric nervous system (ENS) has been shown to retain stem cells, enteric neurogenesis has not previously been demonstrated in adults. The relative number of enteric neurons in wild-type (WT) mice and those lacking 5-HT(4) receptors [knock-out (KO)] was found to be similar at birth; however, the abundance of ENS neurons increased during the first 4 months after birth in WT but not KO littermates. Enteric neurons subsequently decreased in both WT and KO but at 12 months were significantly more numerous in WT. We tested the hypothesis that stimulation of the 5-HT(4) receptor promotes enteric neuron survival and/or neurogenesis. In vitro, 5-HT(4) agonists increased enteric neuronal development/survival, decreased apoptosis, and activated CREB (cAMP response element-binding protein). In vivo, in WT but not KO mice, 5-HT(4) agonists induced bromodeoxyuridine incorporation into cells that expressed markers of neurons (HuC/D, doublecortin), neural precursors (Sox10, nestin, Phox2b), or stem cells (Musashi-1). This is the first demonstration of adult enteric neurogenesis; our results suggest that 5-HT(4) receptors are required postnatally for ENS growth and maintenance.
Liu
Min-Tsai
MT
Department of Pathology and Cell Biology, Columbia University, New York, New York 10032, USA. ml27@columbia.edu
Kuan
Yung-Hui
YH
Wang
Jingwen
J
Hen
René
R
Gershon
Michael D
MD
D053687:Adult Stem Cells / Q000502:physiology; D000375:Aging; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017615:Enteric Nervous System / Q000187:drug effects / Q000254:growth & development / Q000502:physiology*; D041981:Gastrointestinal Tract / Q000294:innervation / Q000502:physiology; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D044422:Receptors, Serotonin, 5-HT4 / Q000235:genetics / Q000378:metabolism*; D058828:Serotonin 5-HT4 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology
C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D007211:Indoles; D058828:Serotonin 5-HT4 Receptor Agonists; D017366:Serotonin Receptor Agonists; D013449:Sulfonamides; D044422:Receptors, Serotonin, 5-HT4; C107556:RS 67506; C105050:tegaserod