The enteric nervous system (ENS) is different in structure and function from any other region of the PNS. We have established that the ENS develops from cells that migrate to the gut from sacral as well as vagal regions of the neural crest and we have identified the pathways they follow. the population of crest-derived colonists that first enters the gut is multipotential. Phenotypic expression by crest-derived precursors in the gut, therefore, depends not only on their lineage, but on signals from the enteric microenvironment. Although we have documented many effects of the bowel on crest cell development, little is known about signaling molecules that mediate these actions. At least some of these molecules may be neurotrophins, because all enteric neurons and transiently catecholaminergic (TC) cells, which are found in the bowel and vagal pathways in mice and rats prior to the development of the ENS, express low affinity nerve growth factor (NGF) receptors (LNGFR). TC cells are the vagal crest-derived precursors of at least a subset of the neurons of the ENS. Since most enteric neurons are not dependent on NGF, the expression of LNGFR suggests that enteric neuronal development may be influenced by neurotrophins other than NGF. (i) This hypothesis will be tested by investigating (by in situ hybridization) whether TC cells and/or enteric neurons express the tyrosine kinase proto-oncogenes, trkA, trkB, or trkC, and thus high affinity neurotrophin receptors. (ii) We will also determine the effects of NGF, brain-derived neurotrophic factor, neurotrophins-3-5, as well as the antagonist, K-252b, on the in vitro development of crest-derived cells isolated from the bowel by immunoselection. The location of cells that synthesize neurotrophins found to be effective will then be explored by in situ hybridization. The possibility that ciliary neurotrophin receptors or themselves act as growth/differentiation factors for enteric neurons will also be investigated. (iii) Monoclonal antibodies (MAbs) that react with surface antigens found in the gut only on TC cells will be used to determine whether all, or only a subset (which we will identify), of enteric neurons develop from TC progenitors. These experiments will employ complement-mediated lysis and immunoselection. The hypothesis (based on the common expression of differentiation antigens [SA]) that there is a common progenitor cell in the enteric and sympatho-adrenal lineages will be tested. We will determine whether enteric progenitors can be made to develop in vitro as sympatho-adrenal cells by exposing them first to factors (basic fibroblast growth factor or retinoic acid) that promote the expression of high affinity receptors and then to NGF. We will also determine if sympatho-adrenal progenitors differentiate as enteric neurons if they develop in the gut. (iv) Finally, we will use retroviral mediated gene transfer to stably label sacral crest-derived cells in the bowel in vivo, to determine if they give rise to neurons, glia, and/or ectomesenchyme, and if an interaction with cells from the vagal crest is required for the normal development of the sacral precursors.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurology B Subcommittee 2 (NEUB)
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Spinella, Giovanna M
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Columbia University (N.Y.)
Internal Medicine/Medicine
Schools of Medicine
New York
United States
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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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