Cerebral dopamine neurotrophic factor is essential for enteric neuronal development, maintenance, and regulation of gastrointestinal transit
Alcmène ChalazonitisZhiShan LiTuan D. PhamJason ChenMeenakshi RaoPäivi LindholmMärt SaarmaMaria LindahlMichael D. Gershon
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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.Keywords:
Enteric Nervous System
BACKGROUND: Accumulating evidence points to the brain-derived neurotrophic factor (BDNF) as a biomarker for neuropsychiatric diseases, such as major depression.Mature BDNF is synthesized from its precursor form, proBDNF.Although BDNF levels in human blood can be measured using commercially available human BDNF ELISA kits, due to limited specificity of the BDNF antibody, these kits are unable to distinguish between proBDNF and mature BDNF.In this study, we measured serum levels of proBDNF and mature BDNF in healthy subjects, using human proBDNF and BDNF ELISA kits, respectively.METHODS: Serum levels of proBDNF and mature BDNF in healthy subjects (n = 40) were measured using the sandwich human proBDNF and BDNF ELISA kits. RESULTS:In healthy subjects, serum levels of mature BDNF were 23.71 ± 5.61 ng/mL (mean ± S.D., n=40).Serum levels of proBDNF in healthy subjects were 7.58 ± 7.68 ng/mL (mean ± S.D., n=25).However in 15 subjects, serum levels of proBDNF were less than the minimum detectable concentration (0.5 ng/mL) of the kit. CONCLUSIONS:This study shows that serum levels of proBDNF and mature BDNF are measurable using either the commercially available human proBDNF or BDNF ELISA kits, although the sensitivity of proBDNF kit was unacceptably low.These ELISA kits may be useful for measuring proBDNF and mature BDNF in the body fluids of patients with neuropsychiatric, cardiovascular and other diseases.
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In 1989 Leitbrock et al. reported the full primary structure of brain-derived neurotrophic factor. The messenger RNA for BDNF was found predominantly in the central nervous system, and the sequence of protein indicated its structural relation to NGF. BDNF belongs to a larger family of neurotrophic molecules. It stimulates the neurite outgrowth and supports neuronal survival.
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Ciliary neurotrophic factor
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Glial cell line-derived neurotrophic factor(GDNF) is a kind of protein factor which can regulate the enteric nervous system in survival, differentiation, colonization and injury repair.It has been confirmed in the disorders of the enteric nervous system, such as hirschsprung and anorectal malformations, but the specific mechanism in regulation of this factor is still unknown.Studies have found that GDNF/GFRa1/RET and GDNF/GFRa1 / NCAM pathway may be involved in the growth and maturation of the enteric nervous system, the disorders of those pathways above may lead to diseases by affecting the differentiation, proliferation and migration of intestinal neural stem cells, causing dysfunctions in the anatomical structure and function of the intestinal neurons.
Key words:
Glial cell line-derived neurotrophic factor; Enteric nervous system; Signal pathway
Enteric Nervous System
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Ret signaling is critical for formation of the enteric nervous system (ENS) because Ret activation promotes ENS precursor survival, proliferation, and migration and provides trophic support for mature enteric neurons. Although these roles are well established, we now provide evidence that increasing levels of the Ret ligand glial cell line-derived neurotrophic factor (GDNF) in mice causes alterations in ENS structure and function that are critically dependent on the time and location of increased GDNF availability. This is demonstrated using two different strains of transgenic mice and by injecting newborn mice with GDNF. Furthermore, because different subclasses of ENS precursors withdraw from the cell cycle at different times during development, increases in GDNF at specific times alter the ratio of neuronal subclasses in the mature ENS. In addition, we confirm that esophageal neurons are GDNF responsive and demonstrate that the location of GDNF production influences neuronal process projection for NADPH diaphorase-expressing, but not acetylcholinesterase-, choline acetyltransferase-, or tryptophan hydroxylase-expressing, small bowel myenteric neurons. We further demonstrate that changes in GDNF availability influence intestinal function in vitro and in vivo. Thus, changes in GDNF expression can create a wide variety of alterations in ENS structure and function and may in part contribute to human motility disorders.
Enteric Nervous System
Proto-Oncogene Proteins c-ret
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Brain-derived neurotrophic factor (BDNF) is a member of neurotrophins family that plays a pivotal role in memory and learning. Brain-derived neurotrophic factor mediates health benefits of physical activity both in humans and animals. The nerve damage and cognitive impairment in diabetic rats are thought to be the result of reduced BDNF levels. The purpose of this study was to examine the effect of short- and long-term moderate forced exercise on BDNF levels in the hippocampus of type 1 diabetic rats.
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Aerobic Exercise
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Мозговой нейротрофический фактор (BDNF) является одним из основных нейротрофических факторов, участвующих в поддержании функционирования и регенерации нервной системы. В последние годы BDNF рассматривают как многообещающую терапевтическую мишень, на основании полученных данных о том, что BDNF улучшает регенерацию нейронов. Цель обзора - суммировать данные об экспрессии BDNF, его сигнализации, эффектах и механизмах стимуляции реиннервации. Анализ исследований последних десятилетий позволяет сделать заключение о целесообразности и перспективности разработок, направленных на создание лекарственных препаратов на основе BDNF для регенерации компонентов нервной системы. Brain-derived neurotrophic factor (BDNF) is a major neurotrophic factor maintaining the nervous system function and regeneration. Based on reports indicating that BDNF enhances neuronal regeneration, in recent years, BDNF has been considered a promising therapeutic target. The aim of this review was to summarize current data on BDNF expression, signaling, and mechanisms for stimulation of reinnervation. Conclusion. Recent studies of the role of BDNF showed that continuation of research and development of BDNF-based drugs stimulating regeneration of nervous system components is advisable and promising.
Reinnervation
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Neuregulin 1 (NRG1) is suggested to promote the survival and maintenance of the enteric nervous system (ENS). As deficiency in its corresponding receptor signaling complex ERBB2/ERBB3 leads to postnatal colonic hypo/aganglionosis we assessed the distributional and expressional pattern of the NRG1-ERBB2/ERBB3 system in the human colon and explored the neurotrophic capacity of NRG1 on cultured enteric neurons. Site-specific mRNA expression of the NRG1-ERBB2/3 system was determined in microdissected samples harvested from enteric musculature and ganglia. Localization of NRG1, ERBB2 and ERBB3 was determined by dual-label-immunohistochemistry using pan-neuronal and pan-glial markers. Morphometric analysis was performed on NRG1-stimulated rat enteric nerve cultures to evaluate neurotrophic effects. mRNA expression of the NRG1-ERBB2/3 system was determined by qPCR. Co-localization of NRG1 with neuronal or synaptic markers was analyzed in enteric nerve cultures stimulated with glial cell line-derived neurotrophic factor (GDNF). The NRG1 system was expressed in both neurons and glial cells of enteric ganglia and in nerve fibers. NRG1 significantly enhanced growth parameters in enteric nerve cell cultures and ErB3 mRNA expression was down-regulated upon NRG1 stimulation. GDNF negatively regulates ErbB2 and ErbB3 mRNA expression. The NRG1-ERBB2/3 system is physiologically present in the human ENS and NRG1 acts as a neurotrophic factor for the ENS. The down-regulation of ErbB3/ErbB2 in GDNF stimulated nerve cell cultures points to an interaction of both neurotrophic factors. Thus, the data may provide a basis to assess disturbed signaling components of the NRG1 system in enteric neuropathies.
neuregulin 1
Enteric Nervous System
Neuregulin
ERBB3
ErbB
ERBB4
Neurturin
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