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PubMed2002

Neurotrophin-3 promotes cell death induced in cerebral ischemia, oxygen-glucose deprivation, and oxidative stress: possible involvement of oxygen free radicals.

To explore the role of neurotrophin-3 (NT-3) during cerebral ischemia, NT-3-deficient brains were subjected to transient focal ischemia. Conditional mutant brains produced undetectable amounts of NT-3 mRNA, whereas the expression of the neurotrophin, BDNF, the NT-3 receptor, TrkC, and the nonselective, low-affinity neurotrophin receptor p75NTR, were comparable to wild-type. Baseline absolute blood flow, vascular and neuroanatomical features, as well as physiological measurements were also indistinguishable from wild-type. Interestingly, the absence of NT-3 led to a significantly decreased infarct volume 23 h after middle cerebral artery occlusion. Consistent with this, the addition of NT-3 to primary cortical cell cultures exacerbated neuronal death caused by oxygen-glucose deprivation. Coincubation with the oxygen free radical chelator, trolox, diminished potentiation of neuronal death. NT-3 also enhanced neuronal cell death and the production of reactive oxygen species caused by oxidative damage inducing agents. We conclude that endogenous NT-3 enhanced neuronal injury during acute stroke, possible by increasing oxygen-radical mediated cell death.

Animals↗

PubMed1997

Specificity determinants in neurotrophin-3 and design of nerve growth factor-based trkC agonists by changing central beta-strand bundle residues to their neurotrophin-3 analogs.

Neurotrophic factors mediate their signal by binding to specific cell surface receptors of the trk family. The binding sites of neurotrophin-3 (NT-3) and nerve growth factor (NGF) to their preferred receptors trkC and trkA, respectively, were previously determined by mutational analyses. These and other studies showed that trkA can discriminate between NGF and NT-3 primarily by recognition of their N-terminal residues. The mechanism of trkC discrimination, however, remained unclear especially since the most important residue in NT-3 involved in binding to trkC, R103, is conserved in all neurotrophins. In this study residues that are part of the central beta-strand bundle of NT-3 and are not conserved among the neurotrophins were grafted onto NGF and tested for recruitment of trkC affinity. Exchange of NGF residues at positions 18, 20, 23, 29, 84, and 86 by their NT-3 counterparts resulted in NGF variants that bound to trkC, while maintaining their affinity to trkA, and were able to induce autophosphorylation and differentiation of PC12 cells expressing trkC. These variants show that the amino acid at position 23 (glycine in NGF, threonine in NT-3) is critical for trkC recognition while other residues fine tune the specificity of NT-3 for trkC. The results demonstrate the importance of nonconserved residues of the central beta-strand bundle region for the interaction of NT-3 with trkC and emphasize the different mechanism of specificity determination that is employed in the NT-3/trkC and NGF/trkA ligand/receptor pairs.

Amino Acid Sequence↗

PubMed2002

Opposing functions of GDNF and NGF in the development of cholinergic and noradrenergic sympathetic neurons.

We identified a population of mature sympathetic neurons in which Ret, the receptor for glial cell line-derived neurotrophic factor (GDNF), is coexpressed with the neurotrophin-3 (NT3) receptor TrkC and choline acetyltransferase. In a complementary population the nerve growth factor receptor TrkA is coexpressed with the norepinephrine transporter. In accordance with these in vivo results, GDNF and neurturin promote the expression of cholinergic marker genes in sympathetic chain explants, similar to NT3 and ciliary neuronotrophic factor (CNTF). To define intracellular signaling mechanisms commonly activated by NT3, GDNF, or CNTF to promote cholinergic differentiation, we have analyzed the activation of intracellular signaling cascades. Signal transducer and activator of transcription-3 (STAT3) was strongly activated by CNTF but not by GDNF or NT3 and hence is not essential for cholinergic differentiation. We conclude that cholinergic properties can be regulated by neurotrophic factors from three different protein families, whereas noradrenergic properties are promoted by NGF.

Acetylcholine↗

PubMed1996

Central infusions of brain-derived neurotrophic factor and neurotrophin-4/5, but not nerve growth factor and neurotrophin-3, prevent loss of the cholinergic phenotype in injured adult motor neurons.

Neurotrophic factors are molecules that prevent neuronal degeneration and regulate neuronal phenotype during either development or adulthood. Relatively little is known about the comparative responsiveness of injured adult central nervous system motor neurons to various neurotrophic factors. In the present study we examined the effects of four members of the neurotrophin family on injured adult motor neurons. Nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3 or neurotrophin-4/5 were infused intracerebroventricularly into adult rats following transection of the motor hypoglossal nerve. Two weeks after axotomy, brain-derived neurotrophic factor and neurotrophin-4/5 completely prevented the loss of the cholinergic phenotype in hypoglossal motor neurons (97 +/- 11% and 99 +/- 5%, respectively) as assessed by choline acetyltransferase immunolabeling. In contrast, nerve growth factor and neurotrophin-3 exerted no protective effect. The low-affinity p75 neurotrophin receptor, capable of binding all four neurotrophins, was re-expressed in injured hypoglossal neurons; the majority of injured hypoglossal neurons also express trkB receptors but not trkA or trkC receptors. Thus, injury-induced responses to neurotrophins in adult motor neurons are mediated by trk receptors and their agonists, but may or may not also require low-affinity p75 neurotrophin receptors. Intracerebroventricular infusions of trkB agonists may be a useful means of targeting multiple and distantly separated populations of motor neurons for neurotrophic factor therapy.

Animals↗

PubMed2003

Protective effect of HSV-mediated gene transfer of nerve growth factor in pyridoxine neuropathy demonstrates functional activity of trkA receptors in large sensory neurons of adult animals.

The distinct distribution of trkA receptors on small neurons and trkC receptors on large neurons in the dorsal root ganglion correlates with the dependence of these two classes of neurons on nerve growth factor and neurotrophin-3, respectively, for survival during development. In adult animals, the distribution of high affinity neurotrophin (trk) is complex and overlapping; neurotrophins are not required for cell survival, but may influence cell phenotype and the response to injury. In order to test the functional activity of trkA receptors in the sensory ganglia of adult animals in vivo, we examined the ability of a nerve growth factor-expressing recombinant replication-defective herpes simplex virus-based vector to prevent the selective degeneration of large sensory fibres caused by intoxication with pyridoxine. Transduction of dorsal root ganglion neurons in vivo by subcutaneous inoculation of the nerve growth factor-expressing vector prevented the development of pyridoxine-induced neuropathy measured by electrophysiological, morphological and behavioural measures. These results demonstrate a functional activity of trkA receptors expressed on large neurons in the dorsal root ganglion in mature animals; this observation has important implications for the choice of neurotrophic factors for treatment of peripheral nerve disease.

Animals↗

PubMed1996

trk-like immunoreactivity in the human trigeminal ganglion and subnucleus caudalis.

The immunohistochemical occurrence of trkA, trkB and trkC receptors was examined in the human trigeminal ganglion and spinal nucleus of subjects at all ages and compared with that of substance P (SP) and calcitonin gene-related peptide (CGRP), trk-like immunoreactive (LI) material was detectable in discrete subpopulations of primary sensory neurones from 25 weeks of gestation to adult life. Each subpopulation overlapped partially with those immunoreactive to SP and CGRP, trkA- and trkC-positive filamentous and punctate elements occurred in the trigeminal subnucleus caudalis. While immunostaining for trkC was restricted to rare isolated elements, that for trkA outlined the superficial laminae of the nucleus and was more intense early in life than in adults.

Aged↗

PubMed1999

Differential expression of trkC mRNA in the chicken embryo from gastrulation to development of secondary brain vesicles.

In situ hybridization revealed that mRNA for the neurotrophin receptor trkC first appears in the chicken embryo at stage 4 anterior to Hensen's node. At stages 6 and 8, trkC mRNA was restricted to the neural plate. By stage 11, trkC mRNA was absent from much of the prosencephalon, the entire mesencephalon and rhombomeres 1 and 4. At stage 15, trkC mRNA expression was limited to rhombomeres 3 and 5, and, by stage 18, there was no apparent expression of trkC mRNA in the hindbrain.

Animals↗

PubMed1999

BDNF and NT4/5 promote survival and neurite outgrowth of pontocerebellar mossy fiber neurons.

The neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3), and NT4/5 are all found in the developing cerebellum. Granule cells, the major target neurons of mossy fibers, express BDNF during mossy fiber synaptogenesis. To determine whether neurotrophins contribute to the development of cerebellar afferent axons, we characterized the effects of neurotrophins on the growth of mossy fiber neurons from mice and rats in vitro. For a mossy fiber source, we used the basilar pontine nuclei (BPN), the major source of cerebellar mossy fibers in mammals. BDNF and NT4/5 increased BPN neuron survival, neurite outgrowth, growth cone size, and elongation rate, while neither NT3 nor NGF increased survival or outgrowth. In addition, BDNF and NT4/5 reduced the size of neurite bundles. Consistent with these effects, in situ hybridization on cultured basilar pontine neurons revealed the presence of mRNA encoding the TrkB receptor which binds both BDNF and NT4/5 with high affinity. We detected little or no message encoding the TrkC receptor which preferentially binds NT3. BDNF and NT4/5 also increased TrkB mRNA levels in BPN neurons. In addition to previously established functions as an autocrine/paracrine trophic factor for granule cells, the present results indicate that cerebellar BDNF may also act as a target-derived trophic factor for basilar pontine mossy fibers.

Afferent Pathways↗

PubMed2003

Neurotrophin-3 and TrkC in the frog visual system: changes after axotomy.

Neurotrophins are potent regulators of the survival of different neuronal populations in the CNS. Little is known of the immunodistribution of neurotrophin-3 (NT-3) and tyrosine kinase C (TrkC) receptor in the frog visual system, which can successfully regenerate and recover vision after injury. In this study we show that both NT-3 and TrkC are present in the frog retina and tectum, and that their distribution changes after optic nerve transection. Both NT-3 and TrkC are present in the ganglion cell layer, inner nuclear layer, nerve fiber layer and outer plexiform layer, and in Müller cells of control retinas. Quantification of identified RGCs shows that there are only small changes in the proportion, or intensity, of NT-3 immunostained cells surviving after axotomy and regeneration. Müller cell staining, however, is increased. TrkC staining in the retina does not change after axotomy. In the tectum, NT-3 immunoreactivity is present in the retinorecipient layer 9, and in radial processes of neurons and ependymoglia. TrkC is present in ependymoglia and in tectal neurons. After axotomy or colchicine treatment fewer NT-3-immunoreactive processes are present in layer 9 and there is decreased staining of tectal neurons. These data are consistent with the hypothesis that NT-3 is synthesized in the retina and anterogradely transported to the tectum. TrkC immunostaining, on the other hand, increases in tectal cells after optic nerve transection, suggesting that it may be regulated by the supply of NT-3 from the retina.

Animals↗

PubMed2005

Immunohistochemical detection of neurotrophin-3 and -4, and their receptors in mouse taste bud cells.

Neurotrophin-3 (NT3) and neurotrophin-4 (NT4) affect the survival and maintenance of central and peripheral neurons. Using an immunohistochemical method, we examined whether the taste bud cells in the circumvallate papillae of normal mice expressed NT3, NT4, and their respective receptors TrkC and TrkB, and if so, what type of cells in the taste buds expressed them. Double immunostaining for either of them and PGP 9.5, NCAM, or gustducin was used to determine which cell types expressed which neurotrophins and receptors. Normal taste bud cells expressed NT3, NT4, and the TrkB receptor, but not TrkC. The percentage of NT3-immunoreactive cells among all taste bud cells was 89.0%, that of NT4-immunoreactive cells, 58.6%, and that of TrkB-immunoreactive cells, 80.8%. Almost none of the NT4-immunoreactive cells were reactive with anti-PGP 9.5 or the anti-NCAM antibody, but they could be stained with anti-gustducin, revealing that NT4-immunoreactive cells were contained only in the type-II--and possibly type-I--cell population. On the other hand, NT3-, and TrkB-immunoreactive cells included type-III cells, together with type-II, -I, and basal cells, because they were positive for PGP 9.5 and gustducin. We conclude that NT4 may exert trophic actions on all types of taste bud cells by binding to their TrkB receptors, and NT3 may also have a similar, though negligible role.

Animals↗

PubMed2004

Neurotrophin-3 and TrkC are expressed in the outflow tract of the developing chicken heart.

Transcripts encoding trkC and full-length (catalytic) TrkC receptors were detected in the outflow tract of the chicken heart during early development (stage 17; embryonic day [E] 2.5) before the start of septation. Expression of trkC mRNA persisted through early septation (stage 25, E4.5-E5) but was no longer evident by the end of septation (stage 34, E8). Neurotrophin-3 (NT-3) mRNA was also shown to be present in the outflow tract throughout cardiac development. Quail-chick chimeras were used to confirm that cardiac neural crest cells were not present in the outflow tract at stage 17 (E2.5). Our results show that NT-3 interacts with cells in the outflow tract that are not of neural crest origin. This finding indicates that, in addition to effects on neural crest cells, NT-3 may be important for cardiac development due to its interaction with cells in the outflow tract such as those arising from the secondary heart field.

Animals↗

PubMed2005

BDNF and NT-3 regulation of trkB and trkC mRNA levels in the developing chick spinal cord.

In this study we investigated the effects of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 on mRNA levels of TrkB and TrkC receptors. We used an expression system to supply developing chicks with the neurotrophic factor and then analysed the receptor mRNA levels at embryonic day 8 (E8), E10 and E15 using semi-quantitative RT-PCR. In control chicks, maximal expression levels of both receptors were observed at E10. Treatment with BDNF resulted in significant down-regulation of TrkB mRNA levels (P<0.05) at E10 but not E8 or E15. Treatment with NT-3 showed down-regulation of trkB levels at all developmental stages. TrkC mRNA levels were down-regulated at all developmental stages with NT-3 treatment and at E10 and E15 with BDNF treatment. For both receptors the down-regulation was greater in NT-3-treated chicks than those treated with BDNF. Thus, our data indicate that neurotrophin receptor mRNA levels in the spinal cord are regulated by neurotrophic factors during embryonic development.

Animals↗

PubMed2000

TrkC expression predicts good clinical outcome in primitive neuroectodermal brain tumors.

PURPOSE: To identify biologic prognostic factors in childhood primitive neuroectodermal tumors (PNET), including medulloblastoma, that accurately define patient groups with sufficiently good prognosis to permit a reduction in treatment intensity. PATIENTS AND METHODS: We determined expression levels of the neurotrophin receptor TrkC mRNA in formalin-fixed tumor samples from 87 well characterized PNET patients using in situ hybridization. Comparison of TrkC mRNA expression levels with clinical and other laboratory variables was performed using univariate and multivariate Cox regression analysis. RESULTS: High TrkC mRNA expression was found to be associated more with higher 5-year cumulative survival rate than was low TrkC mRNA expression (89% v 46%, respectively). When compared with established clinical prognostic factors and laboratory variables of potential prognostic significance, TrkC mRNA expression, by univariate analysis, was found to be the single most powerful predictor of outcome (hazards ratio, 4.81; P <.00005), exceeding all clinical prognostic factors. In multivariate analysis, the hazards ratio remained significant (P <.00005). CONCLUSION: High TrkC mRNA expression in PNET is a powerful independent predictor of favorable clinical outcome. Assessment of TrkC mRNA levels may aid in treatment planning for patients with PNETs and should be incorporated prospectively into PNET clinical trials.

Adolescent↗

PubMed2001

Dissection of NT3 functions in vivo by gene replacement strategy.

The development of the peripheral nervous system is governed in part by a family of neurotrophic factors that signal through Trk tyrosine kinase receptors. Neurotrophin 3 (NT3) ablation in mice causes a more severe neuronal phenotype than deletion of its receptor TrkC, suggesting that NT3 acts also through other non-preferred Trk receptors. To study the role of low-affinity ligand receptor interactions in vivo, we have replaced the Nt3 gene with the gene for brain-derived neurotrophic factor (BDNF), a TrkB ligand. As in NT3 and TrkC null mice, the proprioception system of these mutants failed to assemble. However, sensory fiber projections in the embryonic spinal cord suggest chemotropic effects of BDNF in vivo. In the dorsal root ganglia, the developmental dynamic of neuron numbers demonstrates that NT3 is required for activation of TrkB during neurogenesis and that TrkA is required during target tissue innervation. In the inner ear, the ectopic BDNF rescued the severe neuronal deficits caused by NT3 absence, indicating that TrkB and TrkC activate equivalent pathways to promote survival of cochlear neurons. However, specific increased innervation densities suggest unique functions for BDNF and NT3 beyond promoting neuronal survival. This mouse model has allowed the dissection of specific spatiotemporal Trk receptor activation by NT3. Our analysis provides examples of how development can be orchestrated by complex high- and low-affinity interactions between ligand and receptor families.

Animals↗

PubMed1996

Basophil priming by neurotrophic factors. Activation through the trk receptor.

There is increasing evidence that nerve growth factor (NGF) acts on cells of the immune system, apart from its neurotrophic effects. In human basophils, NGF potentiates mediator release and primes the cells to produce leukotriene C4 in response to C5a. It is, however, unknown whether other homologous neurotrophins also act outside the nervous system, and whether activation of basophils by NGF requires interaction with trk tyrosine kinase receptors, the low affinity NGF receptor (LNGFR), or both. A triple mutant NGF designed to interrupt binding to the LNGFR was found to activate basophils with equal efficacy as wild-type NGF, demonstrating that the LNGFR is not necessary. Despite a 10 times lower potency of mutant NGF, no LNGFR expression was detected by FACS analysis. Brain-derived neurotrophic factor, which interacts with trkB, was inactive at concentrations up to 1000 ng/ml (> 30,000-fold lower potency than NGF), while neurotrophin-3, which is thought to interact with trkC, trkB, and more weakly with trk, induced a threshold effect at 300 ng/ml (approximately 10,000-fold lower potency), demonstrating that 1) the LNGFR cannot deliver a direct signal; and 2) basophils do not express functional trkB and trkC receptors. In agreement with the functional data, basophils (in contrast to other granulocyte types) expressed mRNA for trk, but not trkB or trkC, and no or minimal mRNA for LNGFR. These data demonstrate that human blood basophils express functional trk receptors that do not require the participation of LNGFR, and that, among the neurotrophin family, NGF is unique in priming basophils.

Basophils↗

PubMed2003

Reduction of NT-3 or TrkC results in fewer putative vagal mechanoreceptors in the mouse esophagus.

Intraganglionic laminar endings (IGLEs) represent major vagal afferent structures throughout the gastrointestinal tract. Both morphological and functional data suggested a mechanosensory role. Elucidation of their functional significance in a particular organ would be facilitated by the availability of animal models with significantly altered numbers of IGLEs. The present study was aimed at searching for mouse strains fulfilling this criterion in the esophagus. Anterograde wheat germ agglutinin-horseradish peroxidase tracing (WGA-HRP) from nodose ganglion was used in order to label esophageal IGLEs in mice deficient for neurotrophin-3 (NT-3) or tyrosine kinase C-receptor (TrkC) and in control littermates. This approach was feasible only in heterozygous mutants which are viable. IGLEs were counted in tetramethylbenzidine (TMB) processed wholemounts using a standardised protocol. Quantification of myenteric neurons was done in cuprolinic blue-stained specimens. Nodose neuron counts were performed in cryostat sections stained with cresyl violet. Numbers of IGLEs in the esophagus were significantly reduced in both heterozygous NT-3 (NT-3+/-) and heterozygous TrkC (TrkC+/-) mutants (65% and 40% reduction, respectively). Numbers of nodose neurons were also significantly reduced in NT-3+/- mice (48% reduction), while their reduction in TrkC+/- mutants was insignificant (11% reduction). There was no reduction of myenteric neurons in the esophagus of either mutant strain. The numeric deficiency of IGLEs was unlikely to be secondary to reduction of myenteric neurons. Although only heterozygous mutants could be studied, these results suggest that esophageal IGLEs share neurotrophin dependence on NT-3/TrkC with spinal proprioceptors and some cutaneous mechanosensors. This concurs with their proposed function as vagal mechanosensors crucial for reflex peristalsis.

Animals↗

PubMed2001

Axotomy alters neurotrophin and neurotrophin receptor mRNAs in the vagus nerve and nodose ganglion of the rat.

Neurotrophins and neurotrophin receptors play an important role in survival and growth of injured peripheral nerves. To study the injury-mediated neurotrophic response in autonomic nerves, we investigated changes in mRNA expression of neurotrophins and their receptors in the transected vagus nerve and nodose ganglion. Studies using in situ hybridization histochemistry showed that axotomy of the cervical vagus nerve resulted in increased expression of mRNAs for nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3), and for TrkA, TrkB, and TrkC receptors in non-neuronal cells at both the proximal and distal segments of the transected cervical vagus nerve. Moreover, NGF protein was increased in the distal end, and NT-3 protein was increased in both the proximal and the distal ends of the transected nerve 3 days after axotomy. No change of p75(NTR) mRNA was detected in the transected vagus nerve. The induction of each neurotrophin and Trk receptor mRNA was apparent within 1 day after the axotomy and was sustained at least 14 days. By 45 days after the axotomy, a time when axonal reconnection with target tissue is made (integrity of the nerve-target connection was confirmed by the retrograde transport of FluoroGold from the stomach to vagal cell bodies), the levels of neurotrophin and Trk mRNAs in the vagus nerve declined to pre-axotomy levels. TrkA, TrkC, and p75(NTR) mRNA-containing vagal sensory neurons in the nodose ganglion were reduced in number after cervical vagotomy. Neurotrophin-mRNA-containing neurons were not found in the nodose ganglia from either intact or vagotomized rats. The axotomy-induced up-regulation of neurotrophins and Trk receptors mainly in the non-neuronal cells at or near the site of transection suggests that neurotrophins are involved in the survival and regeneration process of the vagus nerve after injury.

Animals↗

PubMed1998

Bone morphogenetic protein-2 and retinoic acid induce neurotrophin-3 responsiveness in developing rat sympathetic neurons.

Expression of the receptor tyrosine kinase, Trk, determines the specificity of neurotrophin responsiveness of different neuronal populations during development. Recently it has become apparent that sympathetic neurons of rat superior cervical ganglia (SCG) acquire sensitivity to neurotrophin-3 (NT3) before they become dependent on the target-derived nerve growth factor (NGF) for their survival by sequential induction of TrkC and TrkA. The mechanism controlling the expression of TrkC as well as the source of NT3 at their initial developmental stage has, however, not been clarified. Here we show that the treatment of the perinatal rat SCG neurons which express high levels of trkA mRNA with bone morphogenetic protein-2 (BMP2) induced the expression of trkC mRNA. Induction of the functional TrkC receptor by BMP2 was confirmed by the enhancement of the survival response of these neurons to NT3. Treatment of SCG neurons with retinoic acid (RA) promoted the effect of BMP2 on the induction of trkC mRNA levels. BMP2 treatment, on the other hand, promoted the effect of RA on the suppressions of trkA mRNA levels and the NGF-dependent survival of the SCG neurons. Furthermore, BMP2/RA treatment induced the endogenous expression of NT3. These results indicate that specific environmental signals can regulate neurotrophin responsiveness of developing sympathetic neurons by differential alteration of the trk and neurotrophin expressions.

Animals↗