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Results for “Glial Cell Line-Derived Neurotrophic Factor”

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At least 19 recordsLinked to original sources
PubMed1995

Rescue of adult mouse motoneurons from injury-induced cell death by glial cell line-derived neurotrophic factor.

Glial cell line-derived neurotrophic factor (GDNF) has been shown to rescue developing motoneurons in vivo and in vitro from both naturally occurring and axotomy-induced cell death. To test whether GDNF has trophic effects on adult motoneurons, we used a mouse model of injury-induced adult motoneuron degeneration. Injuring adult motoneuron axons at the exit point of the nerve from the spinal cord (avulsion) resulted in a 70% loss of motoneurons by 3 weeks following surgery and a complete loss by 6 weeks. Half of the loss was prevented by GDNF treatment. GDNF also induced an increase (hypertrophy) in the size of surviving motoneurons. These data provide strong evidence that the survival of injured adult mammalian motoneurons can be promoted by a known neurotrophic factor, suggesting the potential use of GDNF in therapeutic approaches to adult-onset motoneuron diseases such as amyotrophic lateral sclerosis.

Animals↗
PubMed1994

Glial cell line-derived neurotrophic factor (GDNF), a new neurotrophic factor for motoneurones.

Glial cell line-derived neurotrophic factor (GDNF) has been postulated to be a specific dopaminergic neurotrophic factor since it selectively enhances the survival of dopaminergic neurones in vitro. We report here that GDNF can also act as a neurotrophic factor for motoneurones. GDNF released by GDNF-transfected BHK cells increases the activity of choline acetyltransferase (ChAT) in cultures from embryonic rat ventral mesencephalon containing cholinergic neurones from cranial motor nuclei and in cultured spinal motoneurones. Furthermore, local application of polymer-encapsulated BHK cells releasing GDNF to transected facial nerve in newborn rats diminishes the death of motoneurones normally occurring after axotomy in the neonatal period. The present results indicate that GDNF may have a therapeutic potential in human motoneurone diseases such as amyotrophic lateral sclerosis.

Animals↗
PubMed1995

Glial cell line-derived neurotrophic factor promotes the survival and morphologic differentiation of Purkinje cells.

Glial cell line-derived neurotrophic factor (GDNF) promotes survival of midbrain dopaminergic neurons and motoneurons. Expression of GDNF mRNA in cerebellum raises the possibility that cells within this structure might also respond to GDNF. To examine potential trophic activities of GDNF, dissociated cultures of gestational day 18 rat cerebellum were grown for < or = 21 days in the presence of factor. GDNF increased Purkinje cell number without affecting the overall number of neurons or glial cells. A maximal response (50% above control) was elicited with GDNF at 1 pg/ml. Effects of GDNF on Purkinje cell differentiation were examined by scoring the morphologic maturation of cells in treated and control cultures. GDNF increased the proportion of Purkinje cells that displayed relatively mature morphologies, characterized by dendritic thickening and the development of spines and filopodial extensions. Morphologic maturation of the overall neuronal population was unaffected. In sum, our data indicate that GDNF is a potent survival and differentiation factor for Purkinje cells, the efferent neurons of cerebellar cortex. Together with its other actions, these findings raise the possibility that GDNF might be a critical trophic factor at multiple loci in neuronal circuits that control motor function.

Animals↗
PubMed1995

The effect of glial cell line-derived neurotrophic factor in fibrin glue on developing dopamine neurons.

Glial cell line-derived neurotrophic factor (GDNF), a member of the transforming growth factor-beta superfamily, promotes the survival, morphological differentiation, and high-affinity dopamine (DA) uptake of cultured nigral DA neurons. In order to test potential methodology for peptide delivery in vivo, GDNF-containing fibrin glue balls (8 micrograms/ball) were incorporated with pieces of fetal ventral mesencephalon (E15) and transplanted into the anterior chambers of sympathetically denervated adult rats. Five weeks after grafting, the numbers of TH-positive neurons and the nerve fiber density were significantly higher in the ventral mesencephalic grafts treated with GDNF-containing glue balls than in those treated with vehicle. In addition, the laminin and GFAP immunoreactivities were similar between the two groups. These data support the concept that GDNF is a potent trophic factor for DA neurons in vivo and suggest that fibrin glue may provide a unique and safe means to permit prolonged delivery of trophic molecules to CNS tissues.

Animals↗
PubMed1995

Glial cell line-derived neurotrophic factor but not transforming growth factor beta 3 prevents delayed degeneration of nigral dopaminergic neurons following striatal 6-hydroxydopamine lesion.

Glial cell line-derived neurotrophic factor (GDNF) and transforming growth factor beta 3 (TGF-beta 3) are members of the TGF-beta superfamily with high neurotrophic activity on cultured nigral dopamine neurons. We investigated the effects of intracerebral administration of GDNF and TGF-beta 3 on the delayed cell death of the dopamine neurons in the rat substantia nigra following 6-hydroxydopamine lesions of dopaminergic terminals in the striatum. Fluorescent retrograde tracer injections and tyrosine hydroxylase immunocytochemistry demonstrated nigral degeneration with an onset 1 week after lesion, leading to extensive death of nigral neurons 4 weeks postlesion. Administration of recombinant human GDNF for 4 weeks over the substantia nigra at a cumulative dose of 140 micrograms, starting on the day of lesion, completely prevented nigral cell death and atrophy, while a single injection of 10 micrograms 1 week postlesion had a partially protective effect. Continuous administration of TGF-beta 3, starting on the day of lesion surgery, did not affect nigral cell death or atrophy. These findings support the notion that GDNF, but not TGF-beta 3, is a potent neurotrophic factor for nigral dopamine neurons in vivo.

Adrenergic Fibers↗
PubMed1995

Retrograde axonal transport of glial cell line-derived neurotrophic factor in the adult nigrostriatal system suggests a trophic role in the adult.

The recently cloned, distant member of the transforming growth factor beta (TGF-beta) family, glial cell line-derived neurotrophic factor (GDNF), has potent trophic actions on fetal mesencephalic dopamine neurons. GDNF also has protective and restorative activity on adult mesencephalic dopaminergic neurons and potently protects motoneurons from axotomy-induced cell death. However, evidence for a role for endogenous GDNF as a target-derived trophic factor in adult midbrain dopaminergic circuits requires documentation of specific transport from the sites of synthesis in the target areas to the nerve cell bodies themselves. Here, we demonstrate that GDNF is retrogradely transported by mesencephalic dopamine neurons of the nigrostriatal pathway. The pattern of retrograde transport following intrastriatal injections indicates that there may be subpopulations of neurons that are GDNF responsive. Retrograde axonal transport of biologically active 125I-labeled GDNF was inhibited by an excess of unlabeled GDNF but not by an excess of cytochrome c. Specificity was further documented by demonstrating that another TGF-beta family member, TGF-beta 1, did not appear to affect retrograde transport. Retrograde transport was also demonstrated by immunohistochemistry by using intrastriatal injections of unlabeled GDNF. GDNF immunoreactivity was found specifically in dopamine nerve cell bodies of the substantia nigra pars compacta distributed in granules in the soma and proximal dendrites. Our data implicate a specific receptor-mediated uptake mechanism operating in the adult. Taken together, the present findings suggest that GDNF acts endogenously as a target-derived physiological survival/maintenance factor for dopaminergic neurons.

Animals↗
PubMed1994

GDNF is expressed in two forms in many tissues outside the CNS.

A recently cloned neurotrophic factor, Glial Cell Line-Derived Neurotrophic Factor (GDNF), has been implicated in the survival and morphological and functional differentiation of midbrain dopaminergic neurones in vitro. GDNF has therefore been proposed as a factor which may have utility in the treatment of Parkinson's disease. In the present study, we have used RT-PCR to analyse the distribution of GDNF mRNA throughout the newborn rat (P0). We show that GDNF transcripts are present in kidney, lung, bone, heart, liver, spleen, sciatic nerve and blood. Two separate GDNF transcripts are present in different ratios in each tissue investigated. Sequence analysis of both these mRNA species revealed that the shorter transcript (sGDNF) contains a deletion of 78 bp in comparison to the published sequence for GDNF. We speculate that this shorter mRNA arose due to alternative splicing.

Amino Acid Sequence↗
PubMed1995

Glial cell line-derived neurotrophic factor supports survival of injured midbrain dopaminergic neurons.

Glial cell-lined derived neurotrophic factor (GDNF) has been shown to promote survival of developing mesencephalic dopaminergic neurons in vitro. In order to determine if there is a positive effect of GDNF on injured adult midbrain dopaminergic neurons in situ, we have carried out experiments in which a single dose of GDNF was injected into the substantia nigra following a unilateral lesion of the nigrostriatal system. Rats were unilaterally lesioned by a single stereotaxic injection of 6-hydroxydopamine (6-OHDA; 9 micrograms/4 microliters normal saline with 0.02% ascorbate) into the medial forebrain bundle and tested weekly for apomorphine-induced (0.05 mg/kg s.c.) contralateral rotation behavior. Rats that manifested > 300 turns/hour received a nigral injection of 100 micrograms GDNF, or cytochrome C as a control, 4 weeks following the 6-OHDA lesion. Rotation behavior was quantified weekly for 5 weeks after GDNF. Rats were subsequently anesthetized, transcardially perfused, and processed for tyrosine hydroxylase immunohistochemistry. It was found that 100 micrograms GDNF decreased apomorphine-induced rotational behavior by more than 85%. Immunohistochemical studies revealed that tyrosine hydroxylase immunoreactivity was equally reduced in the striatum ipsilateral to the lesion in both cytochrome C and GDNF-injected animals. In contrast, large increments in tyrosine hydroxylase immunoreactivity were observed in the substantia nigra of animals treated with 100 micrograms of GDNF, with a significant increase in numbers of tyrosine hydroxylase-immunoreactive cell bodies and neurites as well as a small increase in the cell body area of these neurons. The results suggest that GDNF can maintain the dopaminergic neuronal phenotype in a number of nigral neurons following a unilateral nigrostriatal lesion in the rat.

Animals↗
PubMed1995

Effects of glial cell line-derived neurotrophic factor on developing and mature ventral mesencephalic grafts in oculo.

The search for trophic factors that can support injured dopaminergic neurons and can enhance dopaminergic graft survival and outgrowth for therapeutic uses in Parkinson's disease has lately focused on members of the transforming growth factor (TGF) beta super-family. In this paper we have studied the effects of a member of the TGB beta family, glial cell line-derived neurotrophic factor (GDNF), on immature and mature ventral mesencephalic tissue grafted to the anterior chamber of the eye. The results confirm that GDNF increases survival of TH-positive neurons and enhances TH-immunoreactive nerve fiber formation when the grafts are treated during their development. The distribution of nerve terminals is densest within the area of TH-immunoreactive neurons and at the surface of the grafts. However, there is no change in the number of calcium-binding protein (CaBP)-positive neurons, suggesting that the subpopulation of TH-positive neurons that is increased are the CaBP-negative neurons of the ventral tier of pars compacta. Terminals from those neurons form the striatal patches during normal development. When the grafts are treated with GDNF after maturation, no change in TH-positive cell survival is seen but an increase of nerve terminals is still found within the cell dense area of the graft. Potassium-evoked dopamine release, measured using in vivo chronoamperometry, revealed significantly increased extracellular overflow in transplants treated with GDNF during development. The dopamine uptake blocker nomifensine significantly increased the time for clearance of the released dopamine. These data suggest that GDNF treatment of immature grafts enhances survival of TH-positive neurons, which would have innervated the striatal patches, and also increases TH-immunoreactive nerve fiber formation and dopamine release. Furthermore, GDNF treatment of mature grafts also increases dopamine fiber formation within the TH-positive neuronal area, indicating that adult dopaminergic neurons are also responsive to this agent.

Animals↗
PubMed1995

Spontaneously immortalized adult mouse Schwann cells secrete autocrine and paracrine growth-promoting activities.

We established spontaneously immortalized Schwann cell lines from long-term cultures of adult mouse dorsal root ganglia and peripheral nerves. One of the cell lines, designated IMS32, responded to mitogenic stimuli by platelet-derived growth factor (PDGF)-BB, acidic and basic fibroblast growth factors (aFGF, bFGF), and transforming growth factors (TGF)-beta 1 and -beta 2, as determined by bromodeoxyuridine (BrdU) incorporation and double immunofluorescence for S100 and BrdU. Furthermore, conditioned media (CM) obtained from IMS32 cells showed mitogenic activity for both IMS32 cells and long-term cultured Schwann cells. Western blot analysis revealed TGF-beta-like molecule in the CM, and the activity was absorbed with anti-TGF-beta neutralizing antibody. Reverse transcription followed by polymerase chain reaction (RT-PCR) of IMS32 RNA revealed that these cells expressed TGF-beta 1, -beta 2, and -beta 3 transcripts. When rat pheochromocytoma PC12 cells were incubated with the CM, they developed neurite growth. Coculture of PC12 and IMS32 cells also showed neurite growth of PC12 cells. RNA transcripts of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3), ciliary neurotrophic factor (CNTF), and glial cell line-derived neurotrophic factor (GDNF) were detected from IMS32 cells by RT-PCR. In these, we sequenced the mouse GDNF cDNA coding region and observed 97% and 90% homologies to corresponding rat and human cDNA sequences, respectively. These results indicate that the immortalized Schwann cell line mitotically responds to various growth factors and secretes autocrine and paracrine growth-promoting activities in vitro.

Animals↗
PubMed2026

Long-term rock dove (Columba livia) primordial germ cell culture: A tool towards avian conservation.

Primordial germ cells (PGCs) are critical tools for genome engineering and conservation in birds. Although culture systems for chicken PGCs have been well established for nearly two decades, efforts to propagate PGCs from other avian species have proved exceptionally challenging, limiting the broader application of artificial reproductive technologies in birds. Here we report the first successful derivation and long-term culture of PGCs from the rock dove, or common pigeon (Columba livia). Guided by transcriptomic profiling of PGCs, we developed a species-specific medium that supports PGC maintenance and expansion. We identify insulin signaling as a requirement for survival under the conditions tested, and demonstrate that inhibition of the retinoic acid receptor, in the presence of vitamin A, supports propagation. Supplementation with bone morphogenetic protein 4, leukemia inhibitory factor (LIF), glial cell line-derived neurotrophic factor, and pleiotrophin further enhances PGC proliferation. Cultured cells express canonical germline markers and migrate to the gonads following injection into both rock dove and chicken embryos, confirming functional migratory competency. These findings establish a platform for germline manipulation and biobanking in Columbidae, broadening the potential applicability of reproductive technologies to conservation efforts.

Animals↗
PubMed1995

GDNF is an age-specific survival factor for sensory and autonomic neurons.

Glial cell line-derived neurotrophic factor (GDNF) promotes the survival of two populations of CNS neurons: motoneurons and midbrain dopaminergic neurons. To see whether GDNF promotes the survival of PNS neurons, we studied embryonic chicken autonomic and sensory neurons in culture. We show that GDNF promotes the survival of sympathetic, parasympathetic, proprioceptive, enteroceptive, and small and large cutaneous sensory neurons. Whereas sympathetic, parasympathetic, and proprioceptive neurons become less responsive to GDNF with age, enteroceptive and cutaneous sensory neurons become more responsive. GDNF mRNA is expressed in the tissues innervated by these neurons, and developmental changes in its expression in several tissues mirror the changing responses of the innervating neurons to GDNF. These results show that GDNF promotes the survival of multiple PNS and CNS neurons and suggest that GDNF may be important for regulating the survival of various populations of neurons at different stages of their development.

Animals↗
PubMed1995

Bovine chromaffin cells release a transforming growth factor-beta-like molecule contained within chromaffin granules.

Bovine chromaffin cells contain within their storage vesicles and release upon cholinergic stimulation a complex mixture of proteins and peptides. We present data suggesting that one of these proteins resembles transforming growth factor (TGF)-beta in terms of its biological activity. The assay used to assess the activity of TGF-beta is based on cells transfected with a plasminogen activator inhibitor-1 promoter-luciferase construct. The assay is highly specific in detecting TGF-beta 1, -beta 2, and -beta 3 but does not detect several cytokines and growth factors, such as fibroblast growth factor-2, transforming growth factor-alpha, platelet-derived growth factor-AB, insulin-like growth factor-1, or neurotrophin-3 or -4. Moreover, we show that this assay does not detect a wide range of TGF-beta superfamily members (activin A, bone morphogenetic protein-2, -4, -6, and -7, growth/differentiation factor-5, and glial cell line-derived neurotrophic factor). Chromaffin granules contain approximately 1 ng of TGF-beta/10 mg of protein. The biological activity elicited by the chromaffin granule component can be neutralized by using an antibody against TGF-beta 1/beta 2/beta 3. TGF-beta is releasable from cultured chromaffin cells stimulated with the cholinergic agonist carbachol (10(-5) M). These data suggest that TGF-beta is stored in chromaffin granules and can be released by exocytosis.

Animals↗
PubMed1995

Glutamate regulation of GDNF gene expression in the striatum and primary striatal astrocytes.

The aim of this study was to investigate the regulation of glial cell line-derived neurotrophic factor (GDNF) mRNA by activation of glutamate receptors in the rat striatum. We observed an increase in GDNF mRNA levels in the adult rat striatum after administration of subseizure doses of N-methyl-D,L-aspartic acid (NMA) and kainic acid. Since it is unclear whether the upregulation of GDNF occurred in neurons or astrocytes within the striatum, we further investigated whether GDNF gene expression in primary striatal astrocytes in culture could be regulated by glutamate receptor activation. We found that treatment of the cultures with NMA and kainic acid similarly upregulated GDNF gene expression as observed in vivo, suggesting that striatal astrocytes express functional glutamate receptors. Immunocytochemical and nuclease protection analysis revealed that striatal astrocytes expressed the NMDA-R1 subunit. These findings suggest the regulation of GDNF mRNA in the striatum may be mediated by excitation of glutamate receptors via glutamatergic cortical afferents.

Animals↗
PubMed1994

Transforming growth factor-beta promotes survival of midbrain dopaminergic neurons and protects them against N-methyl-4-phenylpyridinium ion toxicity.

Transforming growth factors beta are multifunctional proteins and regulators of cell proliferation and differentiation. Transforming growth factor-beta s have the capacity to rescue adult neurons from ischemia- and glutamate-induced cell death and are prominent in the embryonic and adult brain including striatum and substantia nigra. In the present study we show that transforming growth factors-beta 1, -2, and -3 promote, in a dose-dependent fashion, in vitro survival of tyrosine hydroxylase-immunoreactive dopaminergic neurons isolated from the embryonic rat mesencephalon floor. The magnitude of the effect, which was half-maximal at a concentration of 20 pM, was identical for all three transforming growth factor-isoforms and matched that of fibroblast growth factor-2. Unlike fibroblast growth factor-2, however, transforming growth factor-beta s did not increase numbers of astroglial cells visualized by using antibodies to glial fibrillary acidic protein, and had no effect on cell proliferation monitored by incorporation of BrdUrd. Transforming growth factor-beta s were significantly more potent than fibroblast growth factor-2 in protecting dopaminergic neurons against N-methyl-4-phenylpyridinium ion toxicity. RT-PCR analysis indicated that the effect of transforming growth factor-beta s is not mediated by glial cell-derived neurotrophic factor, which was not detectable in cultures at various time points. On the other hand transforming growth factor-beta 2 mRNA could be detected in freshly isolated and cultured mesencephalic cells, and its immunoreactivity has also been demonstrated in the embryonic day 14 mesencephalon floor. We conclude that transforming growth factor-beta has trophic and protective effects on developing dopaminergic neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-4-phenylpyridinium↗
PubMed1995

GDNF: existence of a second transcript in the brain.

The detection of the glial cell-line derived neurotrophic factor (GDNF) mRNA by RT-PCR in dissociated cell culture of rat embryonic or post-natal brain allowed the amplification of a doublet. The major band corresponded to the expected size and the minor one to a shorter product. We cloned and sequenced the latter product, and thus identified a mRNA potentially encoding for an isoform of the initially described precursor protein involved in GDNF synthesis.

Animals↗
PubMed1995

Potent inhibitory effects of glial derived neurotrophic factor against kainic acid mediated seizures in the rat.

Recently messenger RNA (mRNA) for glial derived neurotrophic factor (GDNF), a recently discovered member of the TGF-beta superfamily, was shown to increase in the hippocampus after kainic acid-induced seizures. The possibility that exogenous recombinant human (rh) GDNF may have anticonvulsant properties was investigated using a model of temporal lobe epilepsy in the rat. rhGDNF, vehicle or inactive rhGDNF were injected intracerebroventricularly 1 h before peripheral administration of kainic acid. rhGDNF suppressed kainic acid-induced tonic-clonic convulsions when compared to animals treated with vehicle or inactive rhGDNF. The inhibition of kainic acid-induced seizure activity by rhGDNF also prevented the associated neuronal cell loss in hippocampal, thalamic and amygdaloid regions. These results suggest that rhGDNF should be evaluated in other seizure and acute neural disorders that are associated with excitotoxic processes.

Adrenergic Fibers↗