Cerebral Dopamine Neurotrophic Factor Is Essential for Enteric Neuronal Development, Maintenance and Regulation of Gastrointestinal Transit

Alcmène Chalazonitis, ZhiShan Li, Tuan D. Pham, Jason Chen, Meenakshi Rao, Päivi Lindholm, Mart Saarma, Maria Lindahl, Michael D. Gershon

Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu

Abstrakti

Abstract Cerebral dopamine neurotrophic factor (CDNF) is expressed in the brain and is neuroprotective. 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 > myenteric) 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 Cdnf -/- mice. The normal age-related decline in proportions of submucosal dopaminergic neurons is exacerbated in Cdnf -/- animals. The defect in Cdnf -/- animals is not dopamine-restricted; proportions of other submucosal neurons (NOS-, GABA-, and CGRP-expressing), 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-derived cells (ENCDC), which also express the dopamine-related transcription factor Foxa2. Addition of CDNF to ENCDC promotes development of dopaminergic neurons; moreover, survival or these neurons becomes CDNF-dependent after exposure to bone morphogenetic protein 4. The effects of neither glial cell-derived neurotrophic factor (GDNF) nor serotonin are additive with CDNF. We suggest that CDNF plays a critical role in development and long-term maintenance of dopaminergic and other sets of submucosal neurons. This article is protected by copyright. All rights reserved.
Alkuperäiskielienglanti
LehtiJournal of Comparative Neurology
Vuosikertan/a
Numeron/a
ISSN0021-9967
DOI - pysyväislinkit
TilaJulkaistu - 10 maaliskuuta 2020
OKM-julkaisutyyppiA1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä, vertaisarvioitu

Tieteenalat

  • 3124 Neurologia ja psykiatria

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