Glial Cell Line-derived Neurotrophic Factor Signaling Research Articles

Analysis of the effect of adult onset increase of neurotrophic factor GDNF expression in APP‐NL‐G‐F AD mouse model

AbstractBackgroundGradual decline in cholinergic transmission and cognitive function occurs during normal aging, whereas pathological loss of cholinergic function is a hallmark of different types of dementia, including Alzheimer’s disease (AD), Lewy body dementia (LBD), and Parkinson’s disease dementia (PDD). Glial cell line‐derived neurotrophic factor (GDNF) is known to modulate and enhance the dopamine system. However, how endogenous GDNF influences brain cholinergic transmission has remained elusive.MethodRecently we showed that two fold increase in endogenous GDNF expression in Gdnf hypermorphic mice, Gdnf wt/hyper, attenuated age‐associated decline in the cholinergic index and cognitive function observed in Gdnf wt/wt animals. Biochemical analysis revealed that the level of nerve growth factor (NGF), which is important for survival and function of central cholinergic neurons, was significantly increased in several brain areas of old Gdnf wt/hyper miceResultOur results identified endogenous GDNF as a potential enhancer of cholinergic transmission upon aging (11). Here we propose to follow up those results by analyzing the effect of adult onset increase in endogenous GDNF expression on cholinergic index, A‐beta load, NGF expression and cognition in APP‐NLGF mouse model of AD. To accelerate AD onset and to facilitate future studies we have also generated and propose characterization of APP‐NLGF conditional Hypermorph mouse model.ConclusionOur goal is to conclude therapeutic potential of enhanced endogenous GDNF signaling on AD associated cholinergic and cognitive decline to pave way to new dementia treatments based on GDNF mimetics currently under development by several academic and industrial laboratories.

The Regulation of Spermatogonial Stem Cells in an Adult Testis by Glial Cell Line-Derived Neurotrophic Factor.

This review focuses on the in vivo regulation of spermatogonial stem cells (SSCs) in adult testes by glial cell line-derived neurotrophic factor (GDNF). To study adult mouse testes, we reversibly inhibited GDNF stimulation of SSCs via a chemical-genetic approach. This inhibition diminishes replication and increases differentiation of SSCs, and inhibition for 9 days reduces transplantable SSC numbers by 90%. With more sustained inhibition, all SSCs are lost, and testes eventually resemble human testes with Sertoli cell-only (SCO) syndrome. This resemblance prompted us to ask if GDNF expression is abnormally low in these infertile human testes. It is. Expression of FGF2 and FGF8 is also reduced, but some SCO testes contain SSCs. To evaluate the possible rebuilding of an SSC pool depleted due to inadequate GDNF signaling, we inhibited and then restored signaling to mouse SSCs. Partial rebuilding occurred, suggesting GDNF as therapy for men with SCO syndrome.

Reawakening GDNF's regenerative past in mice and humans.

The ability of an animal to regenerate lost tissue and body parts has obviously life-saving implications. Understanding how this ability became restricted or active in specific animal lineages will help us understand our own regeneration. According to phylogenic analysis, the glial cell line-derived neurotrophic factor (GDNF) signaling pathway, but not other family members, is conserved in axolotls, a salamander with remarkable regenerative capacity. Furthermore, comparing the pro-regenerative Spiny mouse to its less regenerative descendant, the House mouse, revealed that the GDNF signaling pathway, but not other family members, was induced in regenerating Spiny mice. According to GDNF receptor expression analysis, GDNF may promote hair follicle neogenesis – an important feature of skin regeneration – by determining the fate of dermal fibroblasts as part of new hair follicles. These findings support the idea that GDNF treatment will promote skin regeneration in humans by demonstrating the GDNF signaling pathway's ancestral and cellular nature.

Glial cell line derived neurotrophic factor in brain repair after focal ischemic stroke.

Glial cell line derived neurotrophic factor in brain repair after focal ischemic stroke.

Eye alignment changes caused by sustained GDNF treatment of an extraocular muscle in infant non-human primates

The ability of sustained treatment of a single extraocular muscle with glial cell line-derived neurotrophic factor (GDNF) to produce a strabismus in infant non-human primates was tested. Six infant non-human primates received a pellet containing GDNF, releasing 2 µg/day for 90 days, on one medial rectus muscle. Eye alignment was assessed up to 6 months. Five of the six animals showed a slow decrease in eye misalignment from the significant exotropia present at birth, ending with approximately 10° of exotropia. Controls became orthotropic. Misalignment averaged 8° three months after treatment ended. After sustained GDNF treatment, few changes were seen in mean myofiber cross-sectional areas compared to age-matched naïve controls. Neuromuscular junction number was unaltered in the medial rectus muscles, but were significantly reduced in the untreated lateral recti. Neuromuscular junctions on slow fibers became multiply innervated after this sustained GDNF treatment. Pitx2-positive cells significantly decreased in treated and contralateral medial rectus muscles. Our study suggests that balanced GDNF signaling plays a role in normal development and maintenance of orthotropia. Sustained GDNF treatment of one medial rectus muscle resulted in a measurable misalignment largely maintained 3 months after treatment ended. Structural changes suggest mechanisms for producing an imbalance in muscle function.

TGF-β1 Increases GDNF Production by Upregulating the Expression of GDNF and Furin in Human Granulosa-Lutein Cells.

Glial cell line-derived neurotrophic factor (GDNF) is expressed at a high level in the human ovary and GDNF signaling is involved in the direct control of follicular activation and oocyte maturation. Transforming growth factor-β1 (TGF-β1) plays an important role in the regulation of various ovarian functions. Furin is an intracellular serine endopeptidase of the subtilisin family that is closely associated with the activation of multiple protein precursors. Despite the important roles of GDNF and TGF-β1 in the regulation of follicular development, whether TGF-β is able to regulate the expression and production of GDNF in human granulosa cells remains to be determined. The aim of this study was to investigate the effect of TGF-β1 on the production of GDNF and its underlying mechanisms in human granulosa-lutein (hGL) cells. We used two types of hGL cells (primary hGL cells and an established immortalized hGL cell line, SVOG cells) as study models. Our results show that TGF-β1 significantly induced the expression of GDNF and furin, which, in turn, increased the production of mature GDNF. Using a dual inhibition approach combining RNA interference and kinase inhibitors against cell signaling components, we showed that the TβRII type II receptor and ALK5 type I receptor are the principal receptors that mediated TGF-β1-induced cellular activity in hGL cells. Additionally, Sma- and Mad-related protein (SMAD)3 and SMAD4 are the downstream signaling transducers that mediate the biological response induced by TGF-β1. Furthermore, furin is the main proprotein convertase that induces the production of GDNF. These findings provide additional regulatory mechanisms by which an intrafollicular factor influences the production of another growth factor through a paracrine or autocrine interaction in hGL cells.

A dual role for peripheral GDNF signaling in nociception and cardiovascular reflexes in the mouse

Group III/IV muscle afferents transduce nociceptive signals and modulate exercise pressor reflexes (EPRs). However, the mechanisms governing afferent responsiveness to dually modulate these processes are not well characterized. We and others have shown that ischemic injury can induce both nociception-related behaviors and exacerbated EPRs in the same mice. This correlated with primary muscle afferent sensitization and increased expression of glial cell line-derived neurotrophic factor (GDNF) in injured muscle and increased expression of GDNF family receptor α1 (GFRα1) in dorsal root ganglia (DRG). Here, we report that increased GDNF/GFRα1 signaling to sensory neurons from ischemia/reperfusion-affected muscle directly modulated nociceptive-like behaviors and increased exercise-mediated reflexes and group III/IV muscle afferent sensitization. This appeared to have taken effect through increased cyclic adenosine monophosphate (cAMP) response element binding (CREB)/CREB binding protein-mediated expression of the purinergic receptor P2X5 in the DRGs. Muscle GDNF signaling to neurons may, therefore, play an important dual role in nociception and sympathetic reflexes and could provide a therapeutic target for treating complications from ischemic injuries.

MicroRNA-204 silencing relieves pain of cervical spondylotic radiculopathy by targeting GDNF.

Cervical spondylosis may cause chronic neck pain, radiculopathy and/or myelopathy, and consequently results in severe brain damage. Glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor for motoneurons. Accumulating microRNAs (miRNAs) have highlighted as critical regulators of GDNF signaling in the mediation of neuroinflammation and neuropathic pain. Hence, we performed this study to investigate the potential role of miR-204 in the neuropathic pain of cervical spondylotic radiculopathy (CSR) by targeting GDNF. A rat model of spinal cord compression (SCC) was established to stimulate a pathologic lesion. RT-qPCR and western blot assays characterized the downregulation of GDNF and the upregulation of miR-204 in spinal cord tissues of rats under the conditions of SCC. Moreover, miR-204 could directly target GDNF, as evidenced by dual-luciferase reporter gene assay. In order to elucidate the roles of miR-204 and GDNF in SCC-induced neuropathic pain, miR-204 sponge, GDNF, or shRNA against GDNF was introduced to the rats, followed by measurements for SCC-induced neuroinflammation and neuropathic pain. GDNF upregulation or miR-204 silencing was identified to reduce the spontaneous pain score, gait scores and cell apoptosis. Furthermore, GDNF upregulation or miR-204 silencing resulted in elevated amplitude of sensory-evoked potentials (SEPs), number of motoneurons, release of pro-inflammatory factors, TNF-α, and IL-1β in addition to an increase in the anti-inflammatory factor BDNF. Taken together, upregulation of GDNF induced by miR-204 silencing confers protection against SCC-induced pain in rat models, suggesting a potential therapeutic target for CSR treatment.

Electroacupuncture Therapy Ameliorates Motor Dysfunction via Brain-Derived Neurotrophic Factor and Glial Cell Line-Derived Neurotrophic Factor in a Mouse Model of Parkinson's Disease.

Parkinson's disease (PD) is characterized by dopaminergic neuron loss in the substantia nigra. However, specific sensory stimulation via electroacupuncture (EA) therapy may attenuate this loss by promoting the expression of endogenous neurotrophic factors in a manner similar to physical therapy. We investigated the potential protective effects of EA on dopaminergic neurons in a mouse model of PD and whether these effects are associated with the promotion of endogenous brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF). Mouse models of PD were generated using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine. Motor performance was assessed using behavioral tests, and Western blot experiments, enzyme-linked immunosorbent assays (ELISAs), and immunohistochemical assays were performed. In both mouse models, EA treatment ameliorated motor impairments and dopaminergic neuron loss; these changes were accompanied by increases in BDNF and GDNF. In the MPTP group, EA treatment improved motor dysfunction by attenuating dopaminergic neuron loss in the substantia nigra, similar to the effects of levodopa. EA treatment significantly upregulated BDNF and GDNF expression in both the substantia nigra and striatum. Moreover, EA treatment induced the expression of cAMP response element binding protein (CREB) as well as Akt and Pitx3 in dopaminergic neurons in the substantia nigra. However, levodopa treatment did not induce BDNF/GDNF activation or related signaling factors. Thus, EA therapy may exert protective effects on dopaminergic neurons by upregulating the expression of BDNF, GDNF, and related signaling factors, thereby improving motor function. Hence, EA may represent an effective adjuvant therapy for motor deficits in patients with PD.

Glial cell line-derived neurotrophic factor (GDNF) mediates hepatic stellate cell activation via ALK5/Smad signalling

ObjectiveAlthough glial cell line-derived neurotrophic factor (GDNF) is a member of the transforming growth factor-β superfamily, its function in liver fibrosis has rarely been studied. Here, we investigated the role...

AKT3 Is a Pivotal Molecule of Cadherin-22 and GDNF Family Receptor-α1 Signal Pathways Regulating Self-Renewal in Female Germline Stem Cells.

Female germline stem cells (FGSCs) are rare population residing in cortex of ovary, with the potential to rescue female infertility caused by ovary failure. Recently, we reported that cadherin-22 (CDH22), a member of cadherin family, regulates self-renewal of mouse FGSCs via interaction with JAK-STAT signal pathway and β-catenin. In this study, the expression profiles of FGSCs and spermatogonial stem cells (SSCs) were analyzed to further reveal their similarity and difference, and AKT3 was predicted as a pivotal molecule for FGSCs self-renewal. Then, we demonstrated that CDH22 interacted with PI3K to phosphorylate AKT3 and subsequently enhanced the expression levels of N-myc and cyclin family in FGSCs to promote self-renewal. Moreover, glial cell line-derived neurotrophic factor (GDNF) was identified as an essential factor for FGSCs self-renewal with a more complicated mechanism: GDNF-GFRA1 activates AKT3 via PI3K or Src family kinase (SFK), and SFK upregulates its target genes, Bcl6b, Etv5, and Lhx1, to promote self-renewal of FGSCs. However, Src, the key intermediate factor for SSCs, was not the functional molecule of SFK family in the GDNF signal network of FGSCs. Based on the observations of bioinformatics analysis and molecular evidence, we demonstrate the underlying links of potential factors which are critical to the self-renewal in FGSC and imply the therapeutic potentials of FGSCs in cure of female infertility. Stem Cells 2019;37:1095-1107.

Neurotrophins and glial cell line-derived neurotrophic factor in the ovary: physiological and pathophysiological implications.

BACKGROUNDNeurotrophins [nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4)] and glial cell line-derived neurotrophic factor (GDNF) are soluble polypeptide growth factors that are widely recognized for their roles in promoting cell growth, survival and differentiation in several classes of neurons. Outside the nervous system, neurotrophin (NT) and GDNF signaling events have substantial roles in various non-neural tissues, including the ovary.OBJECTIVE AND RATIONALEThe molecular mechanisms that promote and regulate follicular development and oocyte maturation have been extensively investigated. However, most information has been obtained from animal models. Even though the fundamental process is highly similar across species, the paracrine regulation of ovarian function in humans remains poorly characterized. Therefore, this review aims to summarize the expression and functional roles of NTs and GDNF in human ovarian biology and disorders, and to describe and propose the development of novel strategies for diagnosing, treating and preventing related abnormalities.SEARCH METHODSRelevant literature in the English language from 1990 to 2018 describing the role of NTs and GDNF in mammalian ovarian biology and phenotypes was comprehensively selected using PubMed, MEDLINE and Google Scholar.OUTCOMESStudies have shown that the neurotrophins NGF, BDNF, NT-3 and NT-4 as well as GDNF and their functional receptors are expressed in the human ovary. Recently, gathered experimental data suggest putative roles for NT and GDNF signaling in the direct control of ovarian function, including follicle assembly, activation of the primordial follicles, follicular growth and development, oocyte maturation, steroidogenesis, ovulation and corpus luteum formation. Additionally, crosstalk occurs between these ovarian regulators and the endocrine signaling system. Dysregulation of the NT system may negatively affect ovarian function, leading to reproductive pathology (decreased ovarian reserve, polycystic ovary syndrome and endometriosis), female infertility and even epithelial ovarian cancers.WIDER IMPLICATIONSA comprehensive understanding of the expression, actions and underlying molecular mechanisms of the NT/GDNF system in the human ovary is essential for novel approaches to therapeutic and diagnostic interventions in ovarian diseases and to develop more safe, effective methods of inducing ovulation in ART in the treatment of female infertility.

Directing GDNF-mediated neuronal signaling with proactively programmable cell-surface saccharide-free glycosaminoglycan mimetics.

A significant barrier to harnessing the power of cell-surface glycosaminoglycans (GAGs) to modulate glial cell-line-derived neurotrophic factor (GDNF) signaling is the difficulty in accessing key GAG structures involved. Here, we report tailored GDNF signaling using synthetic polyproline-based GAG mimetics (PGMs). PGMs deliver the much needed proactive programmability for GDNF recognition and effectively modulate GDNF-mediated neuronal processes in a cellular context.

Gfra1 Underexpression Causes Hirschsprung's Disease and Associated Enterocolitis in Mice.

Background & AimsRET, the receptor for the glial cell line–derived neurotrophic factor (GDNF) family ligands, is the most frequently mutated gene in congenital aganglionic megacolon or Hirschsprung’s disease (HSCR). The leading cause of mortality in HSCR is HSCR-associated enterocolitis (HAEC), which is characterized by altered mucin composition, mucin retention, bacterial adhesion to enterocytes, and epithelial damage, although the order of these events is obscure. In mice, loss of GDNF signaling leads to a severely underdeveloped enteric nervous system and neonatally fatal kidney agenesis, thereby precluding the use of these mice for modeling postnatal HSCR and HAEC. Our aim was to generate a postnatally viable mouse model for HSCR/HAEC and analyze HAEC etiology.MethodsGDNF family receptor alpha-1 (GFRa1) hypomorphic mice were generated by placing a selectable marker gene in the sixth intron of the Gfra1 locus using gene targeting in mouse embryonic stem cells.ResultsWe report that 70%–80% reduction in GDNF co-receptor GFRa1 expression levels in mice results in HSCR and HAEC, leading to death within the first 25 postnatal days. These mice mirror the disease progression and histopathologic findings in children with untreated HSCR/HAEC.ConclusionsIn GFRa1 hypomorphic mice, HAEC proceeds from goblet cell dysplasia, with abnormal mucin production and retention, to epithelial damage. Microbial enterocyte adherence and tissue invasion are late events and therefore unlikely to be the primary cause of HAEC. These results suggest that goblet cells may be a potential target for preventative treatment and that reduced expression of GFRa1 may contribute to HSCR susceptibility.

Peripheral Glial Cell Line-Derived Neurotrophic Factor Facilitates the Functional Recovery of Mechanical Nociception Following Inferior Alveolar Nerve Transection in Rats.

To identify endogenous sources of glial cell line-derived neurotrophic factor (GDNF) at the injury site following inferior alveolar nerve transection (IANX) and to determine whether GDNF signaling promotes the recovery of orofacial pain sensation. Nociceptive mechanical sensitivity of the facial skin was assessed following IANX (n = 10) or sham operation (n = 7). GDNF-positive cells were identified and the amount of GDNF measured in the injured region of IANX rats (n = 10) and in sham rats (n = 10). The number of trigeminal ganglion neurons with regenerated axons and the nociceptive mechanical sensitivity after continuous GDNF administration at the injury site were also assessed in IANX (n = 28) and sham (n = 12) rats. The effect of GDNF neutralization on nociceptive mechanical sensitivity at the injury site was evaluated using a neutralizing antibody (GFRα1 Nab) in four groups: IANX + phosphate-buffered saline (PBS) (n = 6); sham (n = 12); IANX + GDNF (n = 12); and IANX + GDNF + GFRα1 Nab (n = 12). Statistical analyses included one-way and two-way repeated measures analysis of variance followed by post hoc tests or unpaired t tests. The threshold for statistical significance was set at P < .05. Nociceptive mechanical sensitivity was lost over the 5 days following IANX and was recovered by day 13. GDNF was expressed in infiltrating inflammatory cells and had enhanced expression. GDNF administration enhanced axonal regeneration and recovery of nociceptive mechanical sensitivity. GDNF neutralization inhibited the recovery of nociceptive mechanical sensitivity after IANX. GDNF signaling at the injury site facilitates the functional recovery of mechanical nociception following IANX and is an attractive therapeutic target for the functional disturbance of pain sensation.

Cyclical expression of GDNF is required for spermatogonial stem cell homeostasis.

In the murine testis, self-renewal of spermatogonial stem cells (SSCs) requires glial cell line-derived neurotrophic factor (GDNF) secreted from neighboring somatic cells. However, it not clear how GDNF promotes self-renewal in vivo or what downstream signaling pathways are required for SSC maintenance. We found that GDNF is normally expressed cyclically during spermatogenesis. Stage-specific ectopic expression of GDNF caused the accumulation of a GFRA1+ LIN28- Asingle population, which has enhanced SSC activity compared with wild type, suggesting that GDNF normally limits self-renewal to specific stages. Despite the increase in SSC cell number, EdU labeling during steady-stage spermatogenesis, and during recovery after busulfan-mediated spermatogonial depletion, indicated that GDNF promotes self-renewal by blocking differentiation and not by promoting proliferation. Increased GDNF signaling led to increased phosphorylation of AKT3 in undifferentiated spermatogonia, but not of AKT1 or AKT2, and was independent of RPS6 phosphorylation, suggesting that AKT3 functions in SSC self-renewal or progenitor cell expansion.

Constitutive Ret signaling leads to long-lasting expression of amphetamine-induced place conditioning via elevation of mesolimbic dopamine

Addictive drugs enhance dopamine release in the striatum, which can lead to compulsive drug-seeking after repeated exposure. Glial cell line-derived neurotrophic factor (GDNF) is an important regulator of midbrain dopamine neurons, and may play a mechanistic role in addiction-related behaviors. To elucidate the components of GDNF-signaling that contribute to addiction-related behaviors of place preference and its extinction, we utilized two genetically modified GDNF mouse models in an amphetamine-induced conditioned place preference (CPP) paradigm and evaluated how the behavioral findings correlate with dopamine signaling in the dorsal and ventral striatum. We utilized two knock-in mouse strains to delineate contributions of GDNF and Ret signaling using MEN2B mice (constitutively active GDNF receptor Ret), and GDNF hypermorphic mice (enhanced endogenous GDNF expression). The duration of amphetamine-induced CPP was greatly enhanced in MEN2B mice, but not in the GDNF hypermorphic mice. The enhanced duration of CPP was correlated with increased tyrosine hydroxylase (TH) expression and dopamine content in the ventral striatum. Together, our results suggest that downstream components of GDNF signaling, in this case Ret, may mediate persistent drug-seeking behavior through increased TH expression and dopamine levels in the mesolimbic dopamine neurons.

Striatal hypodopamine phenotypes found in transgenic mice that overexpress glial cell line-derived neurotrophic factor.

Glial cell line-derived neurotrophic factor (GDNF) positively regulates the development and maintenance of in vitro dopaminergic neurons. However, the in vivo influences of GDNF signals on the brain dopamine system are controversial and not fully defined. To address this question, we analyzed dopaminergic phenotypes of the transgenic mice that overexpress GDNF under the control of the glial Gfap promoter. Compared with wild-type, the GDNF transgenic mice contained higher levels of GDNF protein and phosphorylated RET receptors in the brain. However, there were reductions in the levels of tyrosine hydroxylase (TH), dopamine, and its metabolite homovanillic acid in the striatum of transgenic mice. The TH reduction appeared to occur during postnatal development. Immunohistochemistry revealed that striatal TH density was reduced in transgenic mice with no apparent signs of neurodegeneration. In agreement with these neurochemical traits, basal levels of extracellular dopamine and high K+-induced dopamine efflux were decreased in the striatum of transgenic mice. We also explored the influences of GDNF overexpression on lomomotor behavior. GDNF transgenic mice exhibited lower stereotypy and rearing in a novel environment compared with wild-type mice. These results suggest that chronic overexpression of GDNF in brain astrocytes exerts an opposing influence on nigrostriatal dopamine metabolism and neurotransmission.

RET-mediated glial cell line-derived neurotrophic factor signaling inhibits mouse prostate development.

In humans and rodents, the prostate gland develops from the embryonic urogenital sinus (UGS). The androgen receptor (AR) is thought to control the expression of morphogenetic genes in inductive UGS mesenchyme, which promotes proliferation and cytodifferentiation of the prostatic epithelium. However, the nature of the AR-regulated morphogenetic genes and the mechanisms whereby AR controls prostate development are not understood. Glial cell line-derived neurotrophic factor (GDNF) binds GDNF family receptor α1 (GFRα1) and signals through activation of RET tyrosine kinase. Gene disruption studies in mice have revealed essential roles for GDNF signaling in development; however, its role in prostate development is unexplored. Here, we establish novel roles of GDNF signaling in mouse prostate development. Using an organ culture system for prostate development and Ret mutant mice, we demonstrate that RET-mediated GDNF signaling in UGS increases proliferation of mesenchyme cells and suppresses androgen-induced proliferation and differentiation of prostate epithelial cells, inhibiting prostate development. We also identify Ar as a GDNF-repressed gene and Gdnf and Gfrα1 as androgen-repressed genes in UGS, thus establishing reciprocal regulatory crosstalk between AR and GDNF signaling in prostate development.

Simultaneous Detection of Both GDNF and GFRα1 Expression Patterns in the Mouse Central Nervous System.

Glial cell line-derived neurotrophic factor (GDNF) is proposed as a therapeutic tool in Parkinson’s disease, addiction-related disorders, and neurodegenerative conditions affecting motor neurons (MNs). Despite the high amount of work about GDNF therapeutic application, the neuronal circuits requiring GDNF trophic support in the brain and spinal cord (SC) are poorly characterized. Here, we defined GDNF and GDNF family receptor-α 1 (GFRα1) expression pattern in the brain and SC of newborn and adult mice. We performed systematic and simultaneous detection of EGFP and LacZ expressing alleles in reporter mice and asked whether modifications of this signaling pathway lead to a significant central nervous system (CNS) alteration. GFRα1 was predominantly expressed by neurons but also by an unexpected population of non-neuronal cells. GFRα1 expression pattern was wider in neonatal than in adult CNS and GDNF expression was restricted in comparison with GFRα1 at both developmental time points. The use of confocal microscopy to imaging X-gal deposits and EGFP allowed us to identify regions containing cells that expressed both proteins and to discriminate between auto and non-autotrophic signaling. We also suggested long-range GDNF-GFRα1 circuits taking advantage of the ability of the EGFP genetically encoded reporter to label long distance projecting axons. The complete elimination of either the ligand or the receptor during development did not produce major abnormalities, suggesting a preponderant role for GDNF signaling during adulthood. In the SC, our results pointed to local modulatory interneurons as the main target of GDNF produced by Clarke’s column (CC) cells. Our work increases the understanding on how GDNF signals in the CNS and establish a crucial framework for posterior studies addressing either the biological role of GDNF or the optimization of trophic factor-based therapies.