Cerebral dopamine neurotrophic factor is essential for enteric neuronal development, maintenance, and regulation of gastrointestinal transit

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, nterstitial 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 This article is protected by copyright. All rights reserved. in development and long-term maintenance of dopaminergic and other sets of submucosal neurons.

Cerebral dopamine neurotrophic factor protects and repairs dopamine neurons by novel mechanism

“…In contrast to classical NTFs, publications demonstrating survival-promoting effects of extracellular CDNF and MANF on naive neurons are limited. Exogenous CDNF was able to support the development and survival of enteric DA neurons originating from enteric neural crest-derived cells in vitro [ 75 ], whereas it did not support the survival of cultured postnatal midbrain DA neurons [ 76 ]. CDNF promoted neither the survival of superior cervical ganglion (SCG) neurons, motoneurons, nor dorsal root ganglion neurons in contrast to nerve growth factor (NGF) [ 20 ].…”

“…Biological functions of CDNF in the nervous system has been studied using mouse and zebrafish knockout models [ 75 , 82 , 83 ]. These studies indicate that CDNF expression is important for the development and maintenance of various neuronal types and circuits rather than specifically for DA neurons.…”

“…Cdnf −/− mice suffered from an age-dependent loss of enteric neurons due to increased neurodegeneration and autophagy observed selectively in the submucosal plexus of the intestinal wall, leading to slowed gastrointestinal motility [ 83 ]. Cdnf expression was found to be necessary for the normal development and survival of enteric DA neurons since Cdnf deletion resulted in loss of DA neuronal markers in the submucosal plexus [ 75 ]. The observed ENS defect in Cdnf −/− mice was not only for DA neurons as the numbers of NOS-, GABA-, and CGRP-expressing neurons were also decreased [ 75 ].…”

Maternal Separation Induced Visceral Hypersensitivity Evaluated via Novel and Small Size Distention Balloon in Post-weaning Mice

“…Indeed, dynamic investigation of the period during early life to adult may, at least partly, contribute to exploring the underlying mechanism of pathogenesis of IBS. Accordingly, with the development of transgenic mice, optogenetic technology, tracing techniques, and so on (Ritsma et al, 2014;Boesmans et al, 2015;Chalazonitis et al, 2020;Liu et al, 2020), the novel distention balloon may be proved useful to explore the potential mechanism of pathogenesis of IBS from early life to adulthood in the future.…”

CDNF and MANF regulate ER stress in a tissue-specific manner

“…Despite the similarities between CDNF and MANF, their respective mouse KO phenotypes differ significantly. Cdnf −/− mice have functional changes in the midbrain dopamine system and display a reduced number of enteric neurons leading to defects in the gastrointestinal transit [ 10 , 11 ]. In contrast, Manf −/− mice in an ICR strain develop severe insulin-dependent diabetes and a drastic growth defect [ 12 ].…”