Study advancement of glial cell line-derived neurotrophic factor in the enteric nervous system
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Abstract:
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 pathwayKeywords:
Enteric Nervous System
Abstract Neurotrophic factors are traditionally recognized for their roles in differentiation, growth, and survival of specific neurons in the central and peripheral nervous system. Some neurotrophic factors are essential for the development and migration of the enteric nervous system along the fetal and post‐natal gut. Over the last two decades, several non‐developmental functions of neurotrophic factors have been characterized. In the adult gastrointestinal tract, neurotrophic factors regulate gut sensation, motility, epithelial barrier function, and protect enteric neurons and glial cells from damaging insults in the microenvironment of the gut. In this issue of Neurogastroenterology and Motility , Fu et al demonstrate that brain‐derived neurotrophic factor plays a role in the pathogenesis of distention‐induced abdominal pain in bowel obstruction. In light of this interesting finding, this mini‐review highlights some of the recent advances in understanding of the physiological and pathophysiological roles of neurotrophic factors in the adult gut.
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Glial cell line-derived neurotrophic factor (GDNF) was first characterized as a survival-promoting factor for dopaminergic neurons. Afterwards, other cells were also discovered to respond to GDNF not only as a survival factor but also as a factor supporting other cellular functions, such as proliferation, differentiation, maturation, neurite outgrowth and other phenomena that have been less studied than survival and are now more extendedly described here in this review. During development, GDNF favors the commitment of neural precursors towards dopaminergic, motor, enteric and adrenal neurons; in addition, it enhances the axonal growth of some of these neurons. GDNF also induces the acquisition of a dopaminergic phenotype by increasing the expression of Tyrosine Hydroxylase, Nurr1 and other proteins that confer this identity and promote further dendritic and electrical maturation. In motor neurons, GDNF not only promotes proliferation and maturation but also participates in regenerating damaged axons and modulates the neuromuscular junction at both presynaptic and postsynaptic levels. Moreover, GDNF modulates the rate of neuroblastoma and glioblastoma cancer cell proliferation. Additionally, the presence or absence of GDNF has been correlated with conditions such as depression, pain, muscular soreness, etc. Although, the precise role of GDNF is unknown, it extends beyond a survival effect. The understanding of the complete range of properties of this trophic molecule will allow us to investigate its broad mechanisms of action to accelerate and/or improve therapies for the aforementioned pathological conditions.
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Slow transit constipation's(STC)etiopathogenisis is not clearly.Enteric nervous system(ENS)is able to independently regulate bowel function and its changes in the slow transit constipation is of great significance.Glial cell line-derived neurotrophic factor not only promotes the survival and differentiation of various neural neurons,but also protects neural injuries caused by a variety of reasons.This review will elaborate the relationship between psychological state and level of activity of enteric nerve system in patients with slow transit constipation.
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Abstract Research stemming from interests in neuronal–glial interactions has led to the identification of a number of novel trophic factors, such as the dopaminergic neurotrophic factor glial cell line‐derived neurotrophic factor (GDNF). Delivery of the GDNF gene to rat models of Parkinson's disease suggests a potential clinical use of GDNF gene therapy for humans with this disease. This review article briefly summarizes the history of GDNF and the effects of GDNF gene delivery prior to or after a lesion of the rat nigrostriatal system.
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Abstract Glial cell line–derived neurotrophic factor (GDNF) is a 134 amino acid protein belonging in the GDNF family ligands (GFLs). GDNF was originally isolated from rat glial cell lines and identified as a neurotrophic factor with the ability to promote dopamine uptake within midbrain dopaminergic neurons. Since its discovery, the potential neuroprotective effects of GDNF have been researched extensively, and the effect of GDNF on motor neurons will be discussed herein. Similar to other members of the TGF-β superfamily, GDNF is first synthesized as a precursor protein (pro-GDNF). After a series of protein cleavage and processing, the 211 amino acid pro-GDNF is finally converted into the active and mature form of GDNF. GDNF has the ability to trigger receptor tyrosine kinase RET phosphorylation, whose downstream effects have been found to promote neuronal health and survival. The binding of GDNF to its receptors triggers several intracellular signaling pathways which play roles in promoting the development, survival, and maintenance of neuron-neuron and neuron-target tissue interactions. The synthesis and regulation of GDNF have been shown to be altered in many diseases, aging, exercise, and addiction. The neuroprotective effects of GDNF may be used to develop treatments and therapies to ameliorate neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). In this review, we provide a detailed discussion of the general roles of GDNF and its production, delivery, secretion, and neuroprotective effects on motor neurons within the mammalian neuromuscular system.
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Dopaminergic neurons of the substantia nigra are vital for proper motor function. The Glial cell line-derived neurotrophic factor (GDNF) family of neurotrophic factors have been shown to promote the survival of dopaminergic neurons both in vitro and in vivo. GDNF and its related factor neurturin have both been trialled as a therapy for Parkinson’s patients for which degeneration of dopaminergic neurons is hallmark pathology. However, GDNF and neurturin are not required for proper development of dopaminergic neurons. Knockout of the GDNF gene in mice causes improper formation of the enteric nervous and kidneys causing death shortly after birth but does not cause any changes in dopaminergic phenotype. Knockout of the neurturin gene is non-lethal but causes abnormalities in enteric, parasympathetic and sensory neurons. No abnormalities in the brain of neurturin knockout have been reported however very little work has been done in this area. It appears that these two neurotrophic factors are not required for successful dopaminergic development.
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Glial cell line-derived neurotrophic factor (GDNF) was initially discovered as a neurotrophic factor that enhances survival of midbrain dopaminergic neurons. Findings in 1994 and 1995 extended the spectrum of biological activities of GDNF to different populations of neurons (motor and sensory). Recent findings revealed that GDNF, Neurturin (NTN), Persephin (PSP), and Artemin (ARTN) are members of the GDNF protein family and are structurally related to transforming growth factor protein family. They are survival factors for peripheral and central neurons, for oligodendrocytes and can promote morphogenesis of kidney in vitro.
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Neurotrophic factors are small proteins necessary for neuron survival and maintenance of phenotype. They are considered as promising therapeutic tools for neurodegenerative diseases. The glial cell line-derived neurotrophic factor (GDNF) protects catecholaminergic cells from toxic insults; thus, its potential therapeutic applicability in Parkinson's disease has been intensely investigated. In recent years, there have been major advances in the analysis of GDNF signaling pathways in peripheral neurons and embryonic dopamine mesencephalic cells. However, the actual physiological role of GDNF in maintaining catecholaminergic central neurons during adulthood is only starting to be unraveled, and the mechanisms whereby GDNF protects central brain neurons are poorly known. In this study, we review the current knowledge of GDNF expression, signaling, and function in adult brain, with special emphasis on the genetic animal models with deficiency in the GDNF-dependent pathways.
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Well-known effects of neurotrophic factors are related to supporting the survival and functioning of various neuronal populations in the body. However, these proteins seem to also play less well-documented roles in glial cells, thus, influencing neuroinflammation. This article summarizes available data on the effects of glial cell line derived neurotrophic factor (GDNF) family ligands (GFLs), proteins providing trophic support to dopaminergic, sensory, motor and many other neuronal populations, in non-neuronal cells contributing to the development and maintenance of neuropathic pain. The paper also contains our own limited data describing the effects of small molecules targeting GFL receptors on the expression of the satellite glial marker IBA1 in dorsal root ganglia of rats with surgery- and diabetes-induced neuropathy. In our experiments activation of GFLs receptors with either GFLs or small molecule agonists downregulated the expression of IBA1 in this tissue of experimental animals. While it can be a secondary effect due to a supportive role of GFLs in neuronal cells, growing body of evidence indicates that GFL receptors are expressed in glial and peripheral immune system cells. Thus, targeting GFL receptors with either proteins or small molecules may directly suppress the activation of glial and immune system cells and, therefore, reduce neuroinflammation. As neuroinflammation is considered to be an important contributor to the process of neurodegeneration these data further support research efforts to modulate the activity of GFL receptors in order to develop disease-modifying treatments for neurodegenerative disorders and neuropathic pain that target both neuronal and glial cells.
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