The enteric nervous system (ENS) is the largest and most complex division of the peripheral nervous system. The ENS is uniquely able to function without input from the CNS. We have demonstrated that enteric neurons are born (undergo terminal mitosis) in a reproducible order in which early-born mature neurons coexist with and innervate still-dividing precursors. Serotonergic and cholinergic neurons are born first, while neurons that contain tyrosine hydroxylase (TH), g-aminobutyric acid (GABA), or calcitonin gene related peptide (CGRP) are born later. This observation led us to frame the hypothesis that the activity of early-born neurons can, through their neurotransmitters, 5-HT and/or acetylcholine (ACh), affect the development of later-born neurons. Supporting of this idea, we showed that 5-HT, through 5-HT4 receptors, promotes development of TH-, GABA-, and CGRP-containing neurons, that these phenotypes are deficient, and the ENS is hypoplastic when tryptophan hydroxylase 2 (TPH2) is deleted and mice thus lack neuronal 5-HT. The late-born neurons are also deficient and the ENS is hypoplastic in animals that carry an autism-associated human variant of the serotonin transporter (SERT; SERT Ala56 or G56A), which is hyperfunctional and clears 5-HT from its receptors too rapidly. In contrast, mice that lack SERT (SERTKO) or which are exposed during development to a SERT inhibitor have a hyperplastic ENS and excessive numbers of late-born neurons. Recent preliminary data, obtained with mice that under- or overexpress the presynaptic choline transporter, suggest that ACh functions like 5-HT. Because serotonergic and cholinergic neurons are thus essential for ENS development, defects in their signaling during ontogeny lead, not only to ENS hypo-or hyperplasia, but to dysmotilities and abnormally regulated mucosal growth that are readily demonstrated in adult animals. We thus postulate that the defects that arise due to errant serotonergic or cholinergic signaling in ontogeny, possibly due to environmental perturbations, contribute to dysmotility disorders in adults. Although TPH2-derived 5-HT is more important than that from TPH1 in ENS formation under basal conditions, TPH1-derived 5-HT from ?pre-enteric? sources, (placenta, yolk sac, and maternal circulation) may be essential to support ENS neurogenesis prior to development of serotonergic neurons. TPH1-derived 5-HT from mucosal enterochromaffin (EC) cells may also disturb ENS neurogenesis and/or function if it reaches the neuronal compartment. We now plan to test 3 overarching hypotheses: (i) ?Pre-enteric? TPH1-derived 5-HT is essential to support enteric neurogenesis before serotonergic neurons develop. (ii) Mucosal SERT activity is essential to prevent 5-HT from overflowing from the mucosa to disturb neurogenesis and/or neuronal function; insults that up- or downregulate SERT thus cause abnormal ENS formation and adult function. (iii) Early-born enteric cholinergic neurons act on muscarinic receptor(s) to stimulate the generation of late-born enteric neurons and also are essential for normal ENS development.

Public Health Relevance

The enteric nervous system (ENS) is very large, complex, and independent in function. The many different types of nerve cell in the ENS develop in a reproducible order; moreover, the activity of the nerve cells that arise first during ENS development influences the development of nerve cells that follow them. As a result, the activity of the early nerve cells, which the environment influences, sculpts subsequent ENS formation, thereby becoming a major determinant of gut behavior. This phenomenon may contribute to the abnormal motility of functional bowel disease and intestinal manifestations of autism spectrum disorder.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Special Emphasis Panel (ZRG1)
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Riddle, Robert D
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Columbia University (N.Y.)
Schools of Medicine
New York
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Gershon, Michael D (2018) Development of the Enteric Nervous System: A Genetic Guide to the Perplexed. Gastroenterology 154:478-480
Robson, Matthew J; Quinlan, Meagan A; Margolis, Kara Gross et al. (2018) p38? MAPK signaling drives pharmacologically reversible brain and gastrointestinal phenotypes in the SERT Ala56 mouse. Proc Natl Acad Sci U S A 115:E10245-E10254
Margolis, Kara G; Buie, Timothy M; Turner, J Blake et al. (2018) Development of a Brief Parent-Report Screen for Common Gastrointestinal Disorders in Autism Spectrum Disorder. J Autism Dev Disord :
Rao, Meenakshi; Gershon, Michael D (2018) Enteric nervous system development: what could possibly go wrong? Nat Rev Neurosci 19:552-565
Khlevner, Julie; Park, Yeji; Margolis, Kara Gross (2018) Brain-Gut Axis: Clinical Implications. Gastroenterol Clin North Am 47:727-739
Israelyan, Narek; Margolis, Kara Gross (2018) Serotonin as a link between the gut-brain-microbiome axis in autism spectrum disorders. Pharmacol Res 132:1-6
Rao, Meenakshi; Rastelli, Daniella; Dong, Lauren et al. (2017) Enteric Glia Regulate Gastrointestinal Motility but Are Not Required for Maintenance of the Epithelium in Mice. Gastroenterology 153:1068-1081.e7
Margolis, Kara Gross (2017) A role for the serotonin reuptake transporter in the brain and intestinal features of autism spectrum disorders and developmental antidepressant exposure. J Chem Neuroanat 83-84:36-40
Israelyan, Narek; Margolis, Kara Gross (2017) KLF-5 extends its fingers to desmosomes: the next frontier for enteric epithelial research? Am J Physiol Gastrointest Liver Physiol 313:G476-G477
Gross Margolis, Kara; Vittorio, Jennifer; Talavera, Maria et al. (2017) Enteric serotonin and oxytocin: endogenous regulation of severity in a murine model of necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol 313:G386-G398

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