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

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

Nerve growth factor is a member of the neurotrophin family of trophic factors that have been reported to be essential for the survival and development of sympathetic neurons and a subset of sensory neurons. Nerve growth factor exerts its effects mainly by interaction with the specific receptor TrkA, which leads to the activation of several intracellular signaling pathways. Once activated, TrkA also allows for a rapid and moderate increase in intracellular calcium levels, which would contribute to the effects triggered by nerve growth factor in neurons. In this report, we analyzed the relationship of calcium to the activation of the Ras/extracellular signal-regulated kinase pathway in PC12 cells. We observed that calcium and calmodulin are both necessary for the acute activation of extracellular signal-regulated kinases after TrkA stimulation. We analyzed the elements of the pathway that lead to this activation, and we observed that calmodulin antagonists completely block the initial Raf-1 activation without affecting the function of upstream elements, such as Ras, Grb2, Shc, and Trk. We have broadened our study to other stimuli that activate extracellular signal-regulated kinases through tyrosine kinase receptors, and we have observed that calmodulin also modulates the activation of such kinases after epidermal growth factor receptor stimulation in PC12 cells and after TrkB stimulation in cultured chicken embryo motoneurons. Calmodulin seems to regulate the full activation of Raf-1 after Ras activation, since functional Ras is necessary for Raf-1 activation after nerve growth factor stimulation and calmodulin-Sepharose is able to precipitate Raf-1 in a calcium-dependent manner.
Mol Cell Biol 2000 Mar
PMID:Nerve growth factor activation of the extracellular signal-regulated kinase pathway is modulated by Ca(2+) and calmodulin. 1068 41

The GDNF family comprises glial cell line-derived neurotrophic factor (GDNF) and the related proteins neurturin, artemin and persephin, which form a subgroup of the TGF-beta superfamily of growth factors. All four neurotrophic factors provide neuronal cell protection and cell survival. GDNF expression was found in the cochlea, and GDNF has been shown to be effective for inner ear protection from drugs and noise-induced insults. As the other members of the GDNF family also provide protective effects on neuronal cells, they may play important roles in the inner ear. We used RT-PCR to examine the expression of GDNF, neurturin, artemin, persephin and their receptors GFRalpha-1, GFRalpha-2, GFRalpha-3 and c-ret in whole rat cochlea as well as in functionally different subfractions (modiolus and sensorineural epithelium/lateral wall) and compared the levels of neurotrophin and receptor mRNAs in the cochlea to those in substantia nigra brain region. Our results demonstrate the expression of all GDNF family members and their receptors in cochlea and substantia nigra. However, the relative levels of mRNA were different for several genes tested in subfractions of the cochlea and/or compared to expression levels in substantia nigra. The presence of mRNA for all four members of the GDNF family and their preferred receptors in the rat cochlea suggests potential functional importance of these neurotrophic factors as protection and survival factors in the inner ear.
Brain Res Mol Brain Res 2000 Mar 10
PMID:Expression of the GDNF family members and their receptors in the mature rat cochlea. 1071 12

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

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

Embryonic sensory and sympathetic neurons that lack neurofibromin, the protein product of the neurofibromatosis type 1 (Nfl) gene, survive and extend neurites in the absence of neurotrophins. To determine whether neurofibromin negatively regulates neurotrophin signaling through its interaction with p21ras, we used Fab antibody fragments to block Ras function in DRG, trigeminal, nodose, and SCG neurons isolated from Nfl(-/-) and wild-type mouse embryos. We show that introduction of anti-Ras Fab fragments significantly reduces the ability of neurofibromin-deficient neurons to survive in the absence of neurotrophins. Moreover, addition of H-ras protein enhances the survival of Nfl(-/-), but not wild-type, DRG neurons. Our results are consistent with a major role for neurofibromin in modulating Trk signaling through p21ras during neuronal development.
Mol Cell Neurosci 2000 Apr
PMID:Neurofibromin negatively regulates neurotrophin signaling through p21ras in embryonic sensory neurons. 1084 75

The MAL proteolipid has been recently demonstrated as being necessary for correct apical sorting of the transmembrane influenza virus hemagglutinin (HA) in Madin-Darby canine kidney (MDCK) cells. The fact that, in contrast to MDCK cells, Fischer rat thyroid (FRT) cells target the majority of glycosylphosphatidylinositol (GPI)-anchored proteins to the basolateral membrane provides us with the opportunity to determine the role of MAL in apical transport of membrane proteins under conditions in which the majority of GPI-anchored proteins are (MDCK cells) or are not (FRT cells) targeted to the apical surface. Using an antisense oligonucleotide-based strategy to deplete endogenous MAL, we have observed that correct transport of apical transmembrane proteins associated (HA) or not (exogenous neurotrophin receptor and endogenous dipeptidyl peptidase IV) with lipid rafts, as well as that of the bulk of endogenous apical membrane, takes place in FRT cells by a pathway that requires normal MAL levels. Even transport of placental alkaline phosphatase, a GPI-anchored protein that is targeted apically in FRT cells, was dependent on normal MAL levels. Similarly, in addition to the reported effect of MAL on HA transport, depletion of MAL in MDCK cells caused a dramatic reduction in the apical delivery of the GPI-anchored gD1-DAF protein, neurotrophin receptor, and the bulk of membrane proteins. These results suggest that MAL is necessary for the overall apical transport of membrane proteins in polarized MDCK and FRT cells.
Mol Biol Cell 2000 Jun
PMID:The MAL proteolipid is necessary for the overall apical delivery of membrane proteins in the polarized epithelial Madin-Darby canine kidney and fischer rat thyroid cell lines. 1084 27

trkC belongs to the trk family of neurotrophin receptors. Several isoforms of trkC have been cloned to date; a full-length catalytic form containing a tyrosine kinase (TK) domain, three full-length isoforms with amino-acid insertions (14, 25, and 39 amino acids) in the TK domain, and five noncatalytic truncated forms that completely lack the TK domain. These isoforms have been studied in several mammalian species, including the pig, rat, mouse, monkey, and human. In this article we report the cloning and sequencing of five trkC isoforms isolated from 30-d postnatal cat visual cortex. The first isoform corresponded to the previously reported full-length trkC transcript containing the 14 amino-acid insert. To search for the presence of other inserts, reverse transcription polymerase chain reaction (RT-PCR) was performed on 30-d postnatal cat visual cortex mRNA using primers that flank the insertion site in the TK domain. Both the isoform containing the 14 amino-acid insert and the isoform lacking any insertion were present in abundant amounts, whereas the other two insert containing isoforms (TK25 and TK39) were much less abundant. The fifth isoform discovered corresponds to the previously reported truncated transcript. Overall, there is a high degree of identity (89-98%) and homology (97-99%) between the cat trkC nucleotide and amino-acid sequences among all mammals. The extracellular juxtamembrane domain was found to be highly divergent among all mammals that have been studied to date. This divergent region also included a proline deletion in the cat trkC sequence. This is the first report of the cloning, sequencing, and RT-PCR analysis of trkC in cat visual cortex, a system extensively studied using anatomical and physiological approaches.
J Mol Neurosci
PMID:Molecular analysis of trkC in the cat visual cortex. 1085 35

Neurexins are a surprisingly diverse group of alternatively spliced proteins possibly involved in neural cell recognition processes. We find neurexin Ialpha and its splice variants highly conserved between mammals and birds. In vivo, neurexin Ialpha is expressed in sympathetic neurons during target innervation and relative expression levels of splice variants change with development. In vitro, no such changes are observed in the absence of growth factors, indicating that interactions with the environment are required to modify the splicing pattern. Specific alterations in splice variant expression are induced in vitro by neurotrophins. Expression patterns of splice variants in vivo and neurotrophin-induced regulation without changes in cell composition in vitro demonstrate that neurexin splice variant expression varies during differentiation of individual neurons. Our data suggest that changes in neurexin splice variants contribute to alterations of neuronal cell surface properties during target innervation.
Mol Cell Neurosci 2000 Jun
PMID:Expression of neurexin Ialpha splice variants in sympathetic neurons: selective changes during differentiation and in response to neurotrophins. 1086 May 82

Previous evidence indicates that both chronic alcohol treatment and traumatic brain injury modulate expression of certain neurotrophins and neurotrophin receptors in cortical tissue. However, the combined effects of chronic alcohol and brain trauma on expression of neurotrophins and their receptors have not been investigated. In the present study, we examined the effects of 6 weeks of chronic ethanol administration on lateral fluid percussion (FP) brain injury-induced alterations in expression of mRNAs for the neurotrophin brain-derived neurotrophic factor (BDNF) and its high affinity receptor, trkB, in rat hippocampus. In both the control- (pair-fed isocaloric sucrose) diet and the chronic ethanol-diet groups, unilateral FP brain injury induced a bilateral increase in levels of both BDNF and trkB mRNAs in the dentate gyrus granule cell layer, and of BDNF mRNA in hippocampal region CA3. However, no significant differences in expression were found between the control-diet and ethanol-diet groups, in either the sham-injured or FP-injured animals. These findings suggest that 6 weeks of chronic ethanol administration does not alter the plasticity of hippocampal BDNF/trkB expression in response to experimental brain injury.
Brain Res Mol Brain Res 2000 Jun 23
PMID:Effects of chronic ethanol administration on expression of BDNF and trkB mRNAs in rat hippocampus after experimental brain injury. 1092 57


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