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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies have identified a multi-component receptor system for the neurotrophic factor, glial cell line-derived neurotrophic factor (GDNF) and its homolog, neurturin (NTN), comprising the signaling tyrosine kinase, Ret and multiple GPI-linked binding proteins, GDNF family receptor alpha-1 and alpha-2 (GFRalpha-1 and GFRalpha-2). In the present study the localization of c-ret and GFRalpha-1 and GFRalpha-2 mRNAs was assessed in the developing rat brain from postnatal day 4 to 70 by in situ hybridization histochemistry, using specific [35S]-labeled oligonucleotides. GFRalpha-1 and GFRalpha-2 mRNAs were differentially distributed throughout the brain at all ages studied, particularly in cerebral cortex, hippocampus, substantia nigra and regions of the thalamus and hypothalamus - both distributions overlapping but different to that of c-ret mRNA. C-ret mRNA was abundant in areas such as the lateral habenula, reticular thalamic nucleus, substantia nigra pars compacta, cranial motor nuclei, and the Purkinje cell layer of the cerebellum. GFRalpha-1 mRNA was abundant in dorsal endopiriform nucleus, medial habenula, reticular thalamic nucleus, pyramidal and granule cell layers of the hippocampus, substantia nigra pars compacta and in cranial motor nuclei. GFRalpha-2 mRNA was highly expressed in many regions including olfactory bulb, lateral olfactory tract nucleus, neocortical layers IV and VI, septum, zona incerta, and arcuate and interpeduncular nuclei. GFRalpha-2 mRNA was detected in the pyramidal cell layers (CA3) of hippocampus at P4 and P7, but was no longer detectable at P14 and beyond, including P70 (adult). GFRalpha-2 mRNA was also detected in Purkinje cells throughout the cerebellum in young postnatal rats, but was enriched in the posterior lobes at P28 and P70. These localization studies support evidence of GDNF/NTN as target-derived and autocrine/paracrine trophic factors in developing brain pathways and earlier suggestions of unique and complex signaling mechanisms for these factors via a family of receptors. Strong expression of GFRalpha-1 and GFRalpha-2 mRNAs in adult brain suggests possible non-trophic functions of GDNF/NTN, as described for other neurotrophins, such as brain-derived neurotrophic factor.
Brain Res Mol Brain Res 1999 Nov 10
PMID:Localization of GDNF/neurturin receptor (c-ret, GFRalpha-1 and alpha-2) mRNAs in postnatal rat brain: differential regional and temporal expression in hippocampus, cortex and cerebellum. 1058 9

In a previous work, we showed that acute intermittent nicotine treatment up-regulates the level of fibroblast growth factor-2 (FGF-2) mRNA in brain regions of tel- and mesencephalon of rats suggesting that neuroprotective effect of (-)nicotine may, at least in part, involve an activation of the neuronal FGF-2 signalling. The present experiments were designed to extend the study on the nicotinic receptor mediated up-regulation of FGF-2 mRNA levels to the use of the potent nicotinic acetylcholine receptor (nAChR) agonist (+/-)-epibatidine. The (+/-)-epibatidine treatment led to a strong and long lasting up-regulation of FGF-2 mRNA expression in the cerebral cortex, in the hippocampal formation, in the striatum and in the substantia nigra. This FGF-2 mRNA induction, already statistically significant at 4 h, peaked at 12 h from treatment and was only partially returned towards normal levels at 48 h, the last time point examined. Using Western blot analysis it was found that the epibatidine-induced upregulation of FGF-mRNA is accompaned by an increase of FGF-2 protein level at the 20-h time-interval. These (+/-)-epibatidine effects on FGF-2 expression were antagonized by the non-competitive nAChR antagonist mecamylamine, indicating an involvement of nicotinic receptors. In the same brain areas examined, no changes were observed in the fibroblast growth factor receptor-1 (FGFR-1) mRNA levels, in brain-derived neurotrophic factor (BDNF) and in glial cell line-derived neurotrophic factor (GDNF) mRNA levels. In view of the neurotrophic function of FGF-2, these results, together with previous ones, could further help to understand the molecular mechanisms mediating the previously observed neuroprotective effects of (-)nicotine.
Brain Res Mol Brain Res 1999 Dec 10
PMID:The nicotinic acetylcholine receptor agonist (+/-)-epibatidine increases FGF-2 mRNA and protein levels in the rat brain. 1064 Jun 80

There are two populations of neurons which are continually renewed in the adult, the dentate gyrus granule neurons and the olfactory bulb granule and periglomerular neurons. In the dentate gyrus, a secondary proliferative zone termed the subgranular zone is established along the interface between the dentate gyrus and the hilus where granule cells are born throughout life. Olfactory bulb neurons are generated in the anterior subventricular zone of the lateral ventricle and migrate via the rostral migratory stream to the olfactory bulb. We examined animals lacking brain-derived neurotrophic factor (BDNF) in order to establish whether this neurotrophin could be involved in the generation and/or survival of these neurons in vivo. We find that cells in nestin-positive regions of both the subgranular layer of the dentate gyrus and the subventricular zone of the olfactory bulb undergo apoptosis starting 2 weeks after birth in the absence of BDNF. However, increased apoptosis was not limited to precursors, as apoptotic cells were also found in the granule cell layer of the dentate gyrus and in the granule and periglomerular layers of the olfactory bulb. The excessive cell death was limited to these populations of neurons as no excessive cell death was detected in other forebrain areas. We conclude that BDNF is essential for the survival of neurons specifically in populations which are continuously being regenerated in the brain.
Brain Res Mol Brain Res 2000 Jan 10
PMID:Cell death in regenerating populations of neurons in BDNF mutant mice. 1064 88

Hippocampal long-term potentiation (LTP) is one of the best-studied models of learning and memory at the molecular level. While it has long been known that tetanic stimulation causes changes at the synapse within seconds to minutes, recent research has begun to focus on factors that may affect synaptic plasticity on a longer time scale. One group of factors with many of the characteristics predicted for both short- and long-term actions at the synapse is the cytokines and growth factors. In vitro, these proteins can alter neuronal morphology, gene expression, and proliferation, and many cytokines and their receptors are present in the adult CNS. Because brain-derived neurotrophic factor (BDNF) is the best-studied synaptic modulator of this class, we begin by discussing the experimental evidence linking BDNF to LTP. Ten cytokines and growth factors that have been examined in the context of hippocampal LTP are then considered. We discuss the effects of LTP on the expression of the cytokines and explore the regulation of synaptic plasticity by exogenous application or antagonist perturbation of these proteins. The available evidence strongly supports a role for these factors in synaptic modulation and should prompt further exploration of their functions at the synapse.
Mol Cell Neurosci 1999 Dec
PMID:Cytokine and growth factor involvement in long-term potentiation. 1058 84

Previous studies have shown that hepatocyte growth factor (HGF) enhances the survival and growth of neurons that depend on NGF for survival. To determine if HGF cooperates with other neurotrophic factors in the developing peripheral nervous system, we studied the effect of HGF on parasympathetic ciliary ganglion neurons and proprioceptive trigeminal mesencephalic nucleus (TMN) neurons, both of which survive with CNTF. HGF did not promote the survival of these neurons on its own but did enhance the number that survived with CNTF and increased the length and branching of their neurite arbors. HGF did not, however, enhance the survival and growth of TMN neurons incubated with BDNF, which promoted their survival as effectively as CNTF. These results show that HGF cooperates with CNTF in promoting the survival and growth of parasympathetic and proprioceptive neurons and that within the same neurons, the effects of HGF on survival and growth are selectively dependent on which other signaling pathways are concurrently activated.
Mol Cell Neurosci 2000 Jan
PMID:Cooperation between HGF and CNTF in promoting the survival and growth of sensory and parasympathetic neurons. 1066 7

BDNF mRNA levels in the hippocampus were studied during the circadian cycle by in situ hybridization. These levels display a circadian pattern, which may be due to regulation by corticosterone. This may have consequences for hippocampal functioning at different time points of the circadian cycle.
Brain Res Mol Brain Res 2000 Feb 22
PMID:Circadian variation in BDNF mRNA expression in the rat hippocampus. 1068 57

Degeneration of serotonergic fibers in the rat striatum was produced by local administration of the serotonergic neurotoxin 5, 7-dihydroxytryptamine (5,7-DHT) or the dopaminergic neurotoxin 1-methyl-4-phenylpyridinium (MPP(+)), which is also toxic to serotonergic neurons. One week before neurotoxin administration, fibroblasts engineered to express the human BDNF gene were grafted into the mesencephalon, dorsal to the substantia nigra. Rats implanted with fibroblasts expressing the LacZ gene were used as controls, as well as sham-operated animals (not injected with any neurotoxin). After a survival period of 1 week, the serotonergic innervation of the striatum was assessed by measuring serotonin (5-HT) content and by immunohistochemical detection of 5-HT positive fibers. BDNF-producing cells prevented the striatal 5-HT loss induced by local administration of either 5,7-DHT or MPP(+), as well as the striatal dopamine (DA) loss induced by the latter neurotoxin. Grafting of fibroblasts carrying the BDNF or the Lac-Z gene did not modify striatal 5-HT or DA content in sham-operated animals. In 5, 7-DHT-lesioned rats, implanted or not with control Lac-Z fibroblasts, a striking reduction in the density of 5-HT immunoreactive fibers was observed. By contrast, the density of 5-HT fibers was similar in rats implanted with BDNF-producing fibroblasts as compared to sham-operated controls. The protective effect of BDNF on the damage to serotonergic terminals induced by the two neurotoxins suggests the interest of this neurotrophin in the treatment of behavioral disorders associated to neurodegenerative diseases.
Brain Res Mol Brain Res 2000 Mar 29
PMID:Implanted BDNF-producing fibroblasts prevent neurotoxin-induced serotonergic denervation in the rat striatum. 1076 6

Alzheimer's disease is a progressive neurodegenerative disorder of the central nervous system. One pathological characteristic is excessive neuronal loss in specific regions of the brain. Among the areas most severely affected are the basal forebrain cholinergic neurons and their projection regions, the hippocampus and cortex. Neurotrophic factors, particularly the neurotrophins nerve growth factor and brain-derived neurotrophic factor, play an important role in the development, regulation and survival of basal forebrain cholinergic neurons. Furthermore, brain-derived neurotrophic factor regulates the function of hippocampal and cortical neurons. Neurotrophins are synthesized in hippocampus and cortex and retrogradely transported to the basal forebrain. Decreased levels of neurotrophic factors are suspected to be involved in the neurodegenerative changes observed in Alzheimer's disease. We examined autopsied parietal cortex samples from age- and gender-matched Alzheimer's diseased and neurologically non-impaired individuals using the quantitative technique of competitive RT-PCR. We demonstrate a 3.4-fold decrease in brain-derived neurotrophic factor mRNA levels in the parietal cortex of patients with Alzheimer's disease compared to controls (p<0.004). A decrease in brain-derived neurotrophic factor synthesis could have detrimental effects on hippocampal, cortical and basal forebrain cholinergic neurons and may account for their selective vulnerability in Alzheimer's disease.
Brain Res Mol Brain Res 2000 Mar 29
PMID:Quantitation of BDNF mRNA in human parietal cortex by competitive reverse transcription-polymerase chain reaction: decreased levels in Alzheimer's disease. 1076 11

Results from several laboratories have suggested that peptide factors known as neurotrophins may play roles coupling changes in synaptic activity to lasting changes in synaptic function. Consistent with this idea, increases in synaptic activity and intracellular calcium induce the expression of the gene that encodes the neurotrophin, brain-derived neurotrophic factor. Recently, a pathway has been elucidated in neurons by which the influx of extracellular calcium evokes brain-derived neurotrophic factor transcription (BDNF). Calcium activates BDNF transcription through two adjacent calcium response elements within one of the promoters of the BDNF gene. One of the two elements binds to the cyclic adenosine monophosphate (AMP) response element binding protein (CREB) transcription factor, and interfering with CREB or related family members inhibits calcium-dependent BDNF transcription. This review focuses on the mechanisms by which calcium influx regulates brain-derived neurotrophic factor expression and the implications that these results have for potential roles of neurotrophins in synaptic function.
Cell Mol Life Sci 2000 Mar
PMID:Calcium regulation of the brain-derived neurotrophic factor gene. 1082 40

Serotonin (5-HT) is an important factor controlling survival, differentiation, and plasticity of neurons in serotonergic target regions of the brain and has been implicated in major psychiatric and autonomic disorders. Relatively little is known, however, of factors controlling differentiation and plasticity of developing and adult 5-HT neurons. We show now that 5-HT, the 5-HT1(A) receptor, brain-derived neurotrophic factor (BDNF), and its receptor, trkB, form an auto/paracrine loop for the regulation of the serotonergic phenotype. Serotonin applied to cultures from E14 rat raphe increased numbers of neurons expressing serotonergic markers in a dose-dependent manner. Agonists of the 5-HT1(A) receptor, BP-554 and 8-OH-DPAT, but not agonists of the 5-HT1(B) and 5-HT1(D) receptors, mimicked this effect, while the specific 5-HT1(A) antagonist, WAY-100635, inhibited it. Serotonin also increased BDNF mRNA and protein in embryonic raphe cultures. Induction of serotonergic markers by serotonin was suppressed by a trkB-IgG fusion protein but not by trkC-IgG. Taken together, our data indicate that serotonin acts on 5-HT1(A) autoreceptors, causing up-regulation of BDNF, which activates trkB to promote serotonergic phenotype-specific markers.
Mol Cell Neurosci 2000 May
PMID:Sequential activation of the 5-HT1(A) serotonin receptor and TrkB induces the serotonergic neuronal phenotype. 1083 1


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