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We have previously shown that CDNF is also expressed in the bowel and that its absence leads to degeneration and autophagy in the enteric nervous system (ENS), particularly in the submucosal plexus. We now demonstrate that enteric CDNF immunoreactivity is restricted to neurons (submucosal\u2009&gt;\u2009myenteric) and is not seen in glia, interstitial cells of Cajal, or smooth muscle. Expression of CDNF, moreover, is essential for the normal development and survival of enteric dopaminergic neurons; thus, expression of the dopaminergic neuronal markers, dopamine, tyrosine hydroxylase, and dopamine transporter are deficient in the ileum of\n                    <jats:italic>Cdnf<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>\u2212\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    mice. The normal age\u2010related decline in proportions of submucosal dopaminergic neurons is exacerbated in\n                    <jats:italic>Cdnf<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>\u2212\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    animals. The defect in\n                    <jats:italic>Cdnf<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>\u2212\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    animals is not dopamine\u2010restricted; proportions of other submucosal neurons (NOS\u2010, GABA\u2010, and CGRP\u2010expressing), are also deficient. The deficits in submucosal neurons are reflected functionally in delayed gastric emptying, slowed colonic motility, and prolonged total gastrointestinal transit. CDNF is expressed selectively in isolated enteric neural crest\u2010derived cells (ENCDC), which also express the dopamine\u2010related transcription factor Foxa2. Addition of CDNF to ENCDC promotes development of dopaminergic neurons; moreover, survival of these neurons becomes CDNF\u2010dependent after exposure to bone morphogenetic protein 4. The effects of neither glial cell\u2010derived neurotrophic factor (GDNF) nor serotonin are additive with CDNF. We suggest that CDNF plays a critical role in development and long\u2010term maintenance of dopaminergic and other sets of submucosal neurons.\n                  <\/jats:p>","DOI":"10.1002\/cne.24901","type":"journal-article","created":{"date-parts":[[2020,3,10]],"date-time":"2020-03-10T09:22:38Z","timestamp":1583832158000},"page":"2420-2444","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Cerebral dopamine neurotrophic factor is essential for enteric neuronal development, maintenance, and regulation of gastrointestinal transit"],"prefix":"10.1002","volume":"528","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4035-1764","authenticated-orcid":false,"given":"Alcm\u00e8ne","family":"Chalazonitis","sequence":"first","affiliation":[{"name":"Department of Pathology and Cell Biology Columbia University, Vagelos College of Physicians and Surgeons  New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"ZhiShan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pathology and Cell Biology Columbia University, Vagelos College of Physicians and Surgeons  New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuan D.","family":"Pham","sequence":"additional","affiliation":[{"name":"Department of Pathology and Cell Biology Columbia University, Vagelos College of Physicians and Surgeons  New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pathology and Cell Biology Columbia University, Vagelos College of Physicians and Surgeons  New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meenakshi","family":"Rao","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Columbia University, Vagelos College of Physicians and Surgeons  New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P\u00e4ivi","family":"Lindholm","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology HiLIFE, University of Helsinki  Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mart","family":"Saarma","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology HiLIFE, University of Helsinki  Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Lindahl","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology HiLIFE, University of Helsinki  Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5893-7643","authenticated-orcid":false,"given":"Michael D.","family":"Gershon","sequence":"additional","affiliation":[{"name":"Department of Pathology and Cell Biology Columbia University, Vagelos College of Physicians and Surgeons  New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,3,26]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn812"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.3727\/0963689IIX600948"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(03)00730-X"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.3233\/JPD-160888"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/cne.23423"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.modgep.2004.08.006"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/PL00007758"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2005.11.012"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1113\/expphysiol.1958.sp001305"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3688-03.2004"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2010.11.017"},{"key":"e_1_2_9_13_1","unstructured":"Chalazonitis A. 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