Cerebral dopamine neurotrophic factor is essential for enteric neuronal development, maintenance, and regulation of gastrointestinal transit. Issue 14 (26th March 2020)

• Record Type: Journal Article
• Authors: Chalazonitis, Alcmène; Li, ZhiShan; Pham, Tuan D.; Chen, Jason; Rao, Meenakshi; Lindholm, Päivi; Saarma, Mart; Lindahl, Maria; Gershon, Michael D.
• Is Part Of: Journal of comparative neurology. Volume 528:Issue 14(2020)
• Page Start: 2420
• Page End: 2444
• Publication Date: 2020-03-26
• Subjects: bone morphogenetic protein‐4 -- dopaminergic neurons -- enteric nervous system -- glial cell line derived neurotrophic factor -- serotonin -- submucosal plexus; Comparative neurobiology -- Periodicals; Neurology -- Periodicals; 616
• DOI: 10.1002/cne.24901
• Languages: English
• ISSNs: 0021-9967

Abstract

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 of 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. Abstract : Cerebral dopamine neurotrophic factor (CDNF) is a member of a novel family of growth factors that is not only secreted but is highly retained in the rough endoplasmic reticulum (ER) and protective against ER stress. CDNF is expressed in the brain and bowel and is neuroprotective. We sought to determine the location of CDNF in the gut as well as its functions during development and maintenance of the enteric nervous system (ENS). The ENS is formed by precursor cells that migrate to the primordial bowel from the neural crest (1). These cells colonize the gut and some of the crest‐derived émigrés express (CDNF) within the gut (2). CDNF selectively promotes the development of subsets of enteric neurons that are late born (3). These include, but are not limited to enteric dopaminergic neurons. Most mature dopaminergic neurons coexpress CDNF. Exposure to bone morphogenetic protein (BMP4) causes neurons isolated from the fetal gut to become CDNF‐dependent. When the bowel contains CDNF, submucosal dopaminergic and other late‐born neurons develop normally and are maintained; however, when CDNF is genetically deleted, these same neurons become deficient as a function of age. Although CDNF is expressed in subsets of neurons in both plexuses, the submucosal plexus selectively becomes hypoplastic in animals lacking CDNF, and parameters of gastrointestinal motility become abnormally slow. We conclude that enteric expression of CDNF is restricted to neurons and their precursors and that CDNF is essential for the development and maintenance of dopaminergic and other late‐born submucosal neurons.