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At least 19 recordsLinked to original sources
PubMed2003

Voluntary exercise increases neurotrophin-3 and its receptor TrkC in the spinal cord.

We have evaluated changes in the expression of neurotrophin-3 (NT-3) and its tyrosine kinase C (TrkC) receptor in the neuromuscular system as a result of voluntary physical activity. We assessed changes in the mRNAs and proteins for NT-3 and TrkC in the lumbar spinal cord and associated soleus muscle following 3 and 7 days of voluntary wheel running. We used quantitative Taqman RT-PCR to measure mRNA and ELISA to assess protein levels. NT-3 mRNA and protein levels increased in the spinal cord to reach statistical significance after 7 days of exercise compared to sedentary control rats. Immunohistochemical analyses localized the elevated NT-3 to the substantia gelatinosa (SG) and nucleus of the dorsal horn. TrkC mRNA levels were significantly elevated in the spinal cord after 3 and 7 days of running. In the soleus muscle, NT-3 mRNA levels and its receptor TrkC were elevated after 3 days, while NT-3 protein levels remained unaffected. The results demonstrate that voluntary exercise has a differential effect on NT-3 as well as its receptor TrkC in the neural and muscular components of the neuromuscular system, and emphasize the role of voluntary activity on the spinal cord and muscle.

Animals↗
PubMed2005

[The role of TrkC receptor and neurotrophin 3 in the development and function of neural cells].

Neurotrophin 3 (NT-3) plays an important role in the development of the nervous system as well as in mediating the survival of neurons in the adult nervous system. NT-3 functions by preferential binding to the cell surface receptor TrkC as well as by binding TrkA, TrkB, and p75(NTR), with lower affinity. Various isoforms of TrkC are generated by alternative splicing. This constitutes, together with ectodomain shedding, an extensive means of regulating TrkC signaling pathways to modulate the effects of NT-3 on target cells during the differentiation of neural cells.

Animals↗
PubMed1996

Constitutive phosphorylation of TrkC receptors in cultured cerebellar granule neurons might be responsible for the inability of NT-3 to increase neuronal survival and to activate p21 Ras.

The neurotrophins brain derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) are both expressed in developing cerebellum in addition to their tyrosine kinase receptors. TrkB and TrkC. In contrast to BDNF.NT-3 has only a negligible or a transient survival activity on cultured cerebellar granule neurons. The granule neurons however, express both TrkC and Trk B receptors which suggests a basic difference in signaling between BDNF and NT-3 in these neurons. Here we have studied whether this difference can be attributed to the presence of alternative TrkC receptor variants on the granule neurons and which signaling pathway is specifically activated by BDNF but not by NT-3 in these neurons. Using RT-PCR it was shown that the cerebellar granule neurons express the full length TrkC receptor, in addition to variant receptors containing small inserts in the receptor tyrosine kinase domain. There was no dramatic change in the relative amounts of different TrkC receptors during development. However, we found the TrkC receptor constitutively phosphorylated even in the absence of added ligand suggesting an interaction of TrkC with endogenously produced NT-3. In addition, NT-3 was able to phosphorylate the BDNF receptor, TrkB but only at higher concentration (50 ng/ml). There were also distinct differences in the activation of intracellular molecules by BDNF and NT-3. Thus, p21 Ras and PLC gamma were activated by BDNF but not by NT-3 whereas both BDNF and NT-3 increased calcium and c-fos mRNA in the granule neurons. These results show that differential activation of specific intracellular pathways such as that of p21 Ras determines the specific effects of BDNF and NT-3 on granule neuron survival. In addition, since calcium is increased by NT-3 in the cerebellar granule neurons, this neurotrophin might have some unknown important effects on these neurons.

Animals↗
PubMed1999

Ontogeny of neurotrophin receptor trkC expression in the rat forebrain and anterior hypothalamus with emphasis on the suprachiasmatic nucleus.

There is little information about neurotrophic regulation in the developing rat hypothalamus. In the present study, we therefore examined the expression of neurotrophin receptor TrkC in the developing forebrain and hypothalamus. In situ hybridization of coronal sections revealed that on the 15th day of gestation, trkC messenger RNA expression is homogeneously distributed over the neocortex, septum, thalamus, hypothalamus, hippocampus, rhinencephalon and the amygdala. Exceptions were the anteroventral nucleus of the hypothalamus and the striatum, which showed higher levels of trkC messenger RNA expression, and the germinal zones which were devoid of trkC messenger RNA. After birth, the homogeneous staining pattern changes into a heterogeneous staining pattern like that found in adulthood. TrkC expression is observed in the area of the suprachiasmatic nucleus as early as E17 and continues until adulthood. The presence of the TrkC receptor in the E17 suprachiasmatic nucleus suggests that neurotrophin-3 plays a role in development of this structure and that application of neurotrophin-3 could stimulate neuronal survival and neuritic outgrowth in a suprachiasmatic nucleus transplantation model.

Animals↗
PubMed1998

Neural differentiation promoted by truncated trkC receptors in collaboration with p75(NTR).

trkC receptors, which serve critical functions during the development of the nervous system, are alternatively spliced to yield isoforms containing the catalytic tyrosine kinase domain (TK+) and truncated isoforms which lack this domain (TK-). To test for potential differences in their roles during early stages of neural development, TK+ and TK- isoforms were ectopically expressed in cultures of neural crest, the stem cell population that gives rise to the vast majority of the peripheral nervous system. NT-3 activation of ectopically expressed trkC TK+ receptors promoted both proliferation of neural crest cells and neuronal differentiation. Strikingly, the trkC TK- isoform was significantly more effective at promoting neuronal differentiation, but had no effect on proliferation. Furthermore, the trkC TK- response was dependent on a conserved receptor cytoplasmic domain and required the participation of the p75(NTR) neurotrophin receptor. Antibody-mediated receptor dimerization of TK+ receptors, but not TK- receptors, was sufficient to stimulate differentiation. These data identify a phenotypic response to activation of the trkC TK- receptor and demonstrate a functional interaction with p75(NTR), indicating there may be multiple trkC receptor-mediated systems guiding neuronal differentiation.

Alternative Splicing↗
PubMed2006

Recombinant adenovirus vector-mediated functional expression of neurotropin-3 receptor (TrkC) in neural stem cells.

We have constructed a recombinant adenovirus expression vector carrying the human neurotrophin-3 (NT-3) receptor TrkC (tyrosine protein kinase C) gene (rAd-TrkC; 2478 bp) and confirmed the expression of the encoded TrkC in green fluorescent protein (GFP)-murine neural stem cells (NSCs) by reverse transcription polymerase chain reaction (RT-PCR), Western blot analysis, and immunocytochemistry. The activity of the expressed rAd-TrkC was verified in vitro by evaluating dose-related responses of NSCs to NT-3, a TrkC specific ligand. TrkC-GFP-NSCs had a significantly higher percentage of neuronal differentiation when treated with NT-3 relative to the rAd-LacZ control cells (55.2% vs. 29.8%; P<0.05, chi(2) test). Thus, our rAd-TrkC vector can transfect NSCs and produce functional TrkC receptors to promote neuronal differentiation of NSCs.

Adenoviridae↗
PubMed1995

Developing inner ear sensory neurons require TrkB and TrkC receptors for innervation of their peripheral targets.

The trkB and trkC genes are expressed during the formation of the vestibular and auditory system. To elucidate the function of trkB and trkC during this process, we have analysed mice carrying a germline mutation in the tyrosine kinase catalytic domain of these genes. Neuroanatomical analysis of homozygous mutant mice revealed neuronal deficiencies in the vestibular and cochlear ganglia. In trkB (-/-) animals vestibular neurons and a subset of cochlear neurons responsible for the innervation of outer hair cells were drastically reduced. The peripheral targets of the respective neurons showed severe innervation defects. A comparative analysis of ganglia from trkC (-/-) mutants revealed a moderate reduction of vestibular neurons and a specific loss of cochlear neurons innervating inner hair cells. No nerve fibres were detected in the sensory epithelium containing inner hair cells. A developmental study of trkB (-/-) and trkC (-/-) mice showed that some vestibular and cochlear fibres initially reached their peripheral targets but failed to maintain innervation and degenerated. TrkB and TrkC receptors are therefore required for the survival of specific neuronal populations and the maintenance of target innervation in the peripheral sensory system of the inner ear.

Animals↗
PubMed1999

Evidence for a role of truncated trkC receptor isoforms in mouse development.

The trkC locus encodes several receptors for neurotrophin-3, including the well studied full-length tyrosine kinase isoform, in addition to receptor isoforms lacking the kinase active domain. TrkC receptors are widely expressed throughout mouse development in many different organs. To investigate the function of truncated receptors in vivo and to identify cell types that are biologically responsive to this gene product, we have overexpressed a physiological truncated trkC isoform in the mouse. Mice overexpressing this receptor develop to term but die in the first postnatal days. High levels of transgene expression result in severe developmental defects in the peripheral nervous system and in the heart. The severity of neuronal losses observed in these animals suggests that truncated receptors may act by sequestering neurotrophin, thus, closely relating this mouse model to the neurotrophin-3-deficient one. Lower levels of exogenous truncated receptor in transgenic mice result in a more modest phenotype and, in some neuronal populations, do not cause neural deficits. Taken together, these data suggest that truncated trkC receptor isoforms may have modulatory functions in development.

Animals↗
PubMed2006

A kinase-deficient TrkC receptor isoform activates Arf6-Rac1 signaling through the scaffold protein tamalin.

Neurotrophins play an essential role in mammalian development. Most of their functions have been attributed to activation of the kinase-active Trk receptors and the p75 neurotrophin receptor. Truncated Trk receptor isoforms lacking the kinase domain are abundantly expressed during development and in the adult; however, their function and signaling capacity is largely unknown. We show that the neurotrophin-3 (NT3) TrkCT1-truncated receptor binds to the scaffold protein tamalin in a ligand-dependent manner. Moreover, NT3 initiation of this complex leads to activation of the Rac1 GTPase through adenosine diphosphate-ribosylation factor 6 (Arf6). At the cellular level, NT3 binding to TrkCT1-tamalin induces Arf6 translocation to the membrane, which in turn causes membrane ruffling and the formation of cellular protrusions. Thus, our data identify a new signaling pathway elicited by the kinase-deficient TrkCT1 receptor. Moreover, we establish NT3 as an upstream regulator of Arf6.

ADP-Ribosylation Factor 6↗
PubMed1994

In situ hybridization of trkB and trkC receptor mRNA in rat forebrain and association with high-affinity binding of [125I]BDNF, [125I]NT-4/5 and [125I]NT-3.

The TrkB and TrkC receptor tyrosine kinases have been identified as high-affinity receptors for the neurotrophic factors brain-derived neurotrophic factor (BDNF) and neurotrophin-4/5 (NT-4/5) and NT-3 respectively. These receptor classes were identified and mapped by the in situ hybridization of antisense riboprobes complementary to portions of the intracellular (tyrosine kinase) or extracellular (ligand-binding) domains of trkB and trkC mRNA, and by the distribution of high-affinity [125I]BDNF, [125I]NT-4/5 and [125I]NT-3 binding sites in adjacent rat brain sections. Both methods showed that TrkB and TrkC receptors are abundant and widely expressed throughout the brain. Kinase or extracellular domain trkC probes labelled neuronal somata in a qualitatively similar manner in virtually every major area of the forebrain. Neither trkC probe labelled non-neuronal cells except for elements within cerebral arteries and arterioles. The kinase domain trkB probe hybridized exclusively to neurons. Neurons expressing trkB were even more widely distributed than those expressing trkC. The extracellular domain trkB probe labelled neurons with the same relative distribution as the trkB kinase domain probe, but also hybridized extensively with non-neural cells, particularly astrocytes, ependyma and choroid epithelium cells. The distribution of [125I]NT-3 binding sites generally resembled that of trkC hybridization, particularly in the neocortex, striatum and thalamus. [125I]BDNF and [125I]NT-4/5 binding sites were more widely distributed and denser than those for [125I]NT-3, and resembled the trkB hybridization pattern. These patterns are consistent with the preferential binding in the brain of TrkC receptors by [125I]NT-3 and of TrkB receptors by [125I]BDNF and [125I]NT-4/5. That the predominantly neuronal patterns of hybridization obtained with kinase and extracellular domain probes for trkC are qualitatively indistinguishable suggests that truncated and full-length forms of TrkC are expressed within extensively overlapping populations of neurons. In marked contrast to TrkC, expression of the full-length and truncated forms of TrkB appears to be largely segregated, being expressed principally on neurons and non-neuronal cells respectively. The abundant and widespread neuronal distribution of full-length, signal-transducing forms of TrkB and TrkC predict that their cognate ligands, BDNF, NT-4/5 and NT-3, may exert direct effects on a large proportion of neurons within the mature brain.

Animals↗
PubMed2005

Haploinsufficiency for trkB and trkC receptors induces cell loss and accumulation of alpha-synuclein in the substantia nigra.

The neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) have been shown to promote survival and differentiation of midbrain dopaminergic (DAergic) neurons in vitro and in vivo. This is consistent with their expression and that of their cognate receptors, trkB and trkC, in the nigrostriatal system. Degeneration of DAergic neurons of the substantia nigra and alpha-synuclein-positive aggregates in the remaining substantia nigra (SN) neurons are hallmarks of Parkinson's disease (PD). Reduced expression of BDNF has been reported in the SN from PD patients. Moreover, mutations in the BDNF gene have been found to play a role in the development of familial PD. We show now that haploinsufficiencies of the neurotrophin receptors trkB and/or trkC cause a reduction in numbers of SN neurons in aged (21-23 month old) mice, which is accompanied by a reduced density in striatal tyrosine hydroxylase immunoreactive (TH-ir) fibers. These aged mutant mice, in contrast to wild-type littermates, display an accumulation of alpha-synuclein in the remaining TH-positive neurons of the SN. We conclude that impairment in trkB and/or trkC signaling induces a phenotype in the aged SN, which includes two hallmarks of PD, losses of TH positive neurons and axons along with massive neuronal deposits of alpha-synuclein.

Aging↗
PubMed1996

Expression of mRNA for the neurotrophin receptor trkC in neuroblastomas with favourable tumour stage and good prognosis.

Childhood neuroblastoma tumours of the sympathetic nervous system show a remarkable clinical heterogeneity ranging from spontaneous regression to unfavourable outcome despite intensive therapy. Favourable neuroblastomas often express high levels of trkA mRNA, encoding the tyrosine kinase receptor for nerve growth factor. We have investigated mRNA expression for the neurotrophin receptor trkC in 23 primary neuroblastomas using a sensitive RNAase protection assay. TrkC expression was detected in 19 of these tumours at highly variable levels with a 300-fold difference between the highest and lowest values. Significantly higher levels of trkC mRNA were found in tumours from patients with favourable features such as low age (P < 0.012), favourable tumour stage (P < 0.012) and favourable prognosis (P < 0.05). Children with intermediate or high trkC mRNA expression had better prognosis compared with those with low or undetectable levels (83.3% vs 20%, P = 0.005). Further characterisation of trkC mRNA expression by reverse transcriptase-polymerase chain reaction (RT-PCR) showed that mRNA encoding the full-length cytoplasmic tyrosine kinase domain of the receptor was only expressed in a subset of favourable tumours. These data show that favourable neuroblastomas may express the full trkC receptor while advanced tumours, in particular MYCN-amplified neuroblastoma, seem to either express no trkC or truncated trkC receptors of as yet unknown biological function. These data are suggestive of a role for trkC and its preferred ligand neutotrophin-3, NT-3, in neuroblastoma differentiation and/or regression.

Age Factors↗
PubMed1999

Activation of neurotrophin-3 receptor TrkC induces apoptosis in medulloblastomas.

Elevated expression of the neurotrophin-3 (NT-3) receptor TrkC by childhood medulloblastomas is associated with favorable clinical outcome. Here, we provide evidence that TrkC is more than simply a passive marker of prognosis. We demonstrate that: (a) medulloblastomas undergo apoptosis in vitro when grown in the presence of NT-3; (b) overexpression of TrkC inhibits the growth of intracerebral xenografts of a medulloblastoma cell line in nude mice; and (c) trkC expression by individual tumor cells is highly correlated with apoptosis within primary medulloblastoma biopsy specimens. TrkC-mediated NT-3 signaling promotes apoptosis by activating multiple parallel signaling pathways and by inducing immediate-early gene expression of both c-jun and c-fos. Considered collectively, these results support the conclusion that the biological actions of TrkC activation affect medulloblastoma outcome by inhibiting tumor growth through the promotion of apoptosis.

Animals↗
PubMed1996

Neurotrophin activates signal transduction in oligodendroglial cells: expression of functional TrkC receptor isoforms.

The role of the NT-3 has been implicated in the survival of progenitor oligodendrocytes in culture. The object of this study was to investigate the expression of the TrkC receptor and its responsiveness in glial cells. We report the expression of two TrkC receptor isoforms in rat primary oligodendrocyte cultures, a glial progenitor cell line, CG-4, and in C6 glioma cells. The reverse transcription-polymerase chain reaction-aided amplification of glial trkC with specific primers from the kinase domain, followed by its cloning and sequencing, shows the presence of two trkC transcripts. The sequence of one of the transcripts is homologous to a previously identified trkC isoform which encodes a functional receptor. The other transcript contains a 42-bp insert in the kinase domain. A Western blot of CG-4 and C6 probed with antibody to a TrkC revealed the presence of gp145-kDa protein band. The investigations revealed a rapid autophosphorylation of gp145TrkC in CG-4 and C6 cells in the presence of its specific ligand, NT-3. Furthermore, K252a, a neurotrophin-specific inhibitor, abolishes the NT-3-mediated receptor autophosphorylation. We also examined other NT-3-dependent phosphorylation of cellular substrates in oligodendroglial cells. Interestingly, we observed phosphorylation of phospholipase C gamma-1 in CG-4 and C6 cells, and phosphorylation of phosphatidylinositol 3-kinase in C6 cells in the presence of NT-3. Both the NT-mediated phosphorylation of phospholipase C gamma-1 and phosphorylation of phosphatidylinositol 3-kinase are blocked in the presence of K252a. The detection of the NT-3-mediated early signal transduction events demonstrates that TrkC receptor exhibits NT-3-mediated intracellular response in oligodendroglial cells.

Animals↗
PubMed1994

Isoforms of the avian TrkC receptor: a novel kinase insertion dissociates transformation and process outgrowth from survival.

TrkC receptor isoforms have been identified by cDNA cloning and RT-PCR analysis of embryonic chick brain RNA. An N-terminal truncation motif is missing from the signal sequence and first cysteine cluster of the extracellular domain. Within the cytoplasmic dimain, a kinase truncation motif retains part of the kinase domain, but appeared to lack activity. Finally, a kinase insert (KI) motif introduces a 25 amino acid sequence distinct from the known mammalian inserts. KI receptors, like full-length receptors, were tyrosine phosphorylated in response to NT-3 and mediated the transformation of chick embryo fibroblasts and process outgrowth from rat PC12 cells. However, KI receptors supported little, if any, survival of serum-deprived PC12 cells. These results indicate that alternative splicing of trkC transcripts is an important mechanism for regulating cellular responses to NT-3.

Alternative Splicing↗
PubMed1999

Mice lacking NT-3, and its receptor TrkC, exhibit profound deficiencies in CNS glial cells.

Neurotrophin-3 (NT-3) and its receptor TrkC are known to be important for neuronal survival. More recently, NT-3 has been implicated as playing a role in oligodendrocyte (OL) proliferation and survival in vitro. Examination of NT-3 and TrkC knockout mice revealed a reduction in NT-3-dependent neurons. To date, no study has examined alterations in glial cell populations in these knockout mice. In this report, we demonstrate a decline in OL progenitor cell numbers within the CNS of NT-3 and TrkC knockout mice. We also observed that immature and mature OL-specific markers were attenuated in the NT-3 and TrkC knockout animals. Deficiencies in other CNS glial cells, including astrocytes and ameboid microglia, were also observed. The subventricular zone (SVZ), a highly proliferative region for progenitor glial cells, was reduced in size. Furthermore, a nuclear-specific stain revealed a decline in the numbers of pyknotic nuclei in and around the SVZ of the knockout mice. These data will support an in vivo NT-3-dependent mechanism for the normal development of CNS glial cells.

Animals↗
PubMed1994

Interactions of neurotrophin-3 (NT-3), brain-derived neurotrophic factor (BDNF), and the NT-3.BDNF heterodimer with the extracellular domains of the TrkB and TrkC receptors.

Interactions of three neurotrophin dimers, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and a NT-3.BDNF heterodimer with extracellular, soluble TrkB and TrkC receptors were studied using native gels, light scattering, and sedimentation equilibrium. These three neurotrophins showed binding of two TrkB receptors per neurotrophin dimer, with a tendency to dissociate into one TrkB per dimer for NT-3 and the heterodimer, as determined by native gels, light scattering, and sedimentation equilibrium. For TrkC, native gels suggested binding of NT-3, heterodimer, and BDNF but not of nerve growth factor. Sedimentation equilibrium revealed that all three neurotrophin molecules bind to TrkC at two receptors per dimer but that BDNF binds much more weakly and that the heterodimer has an intermediate binding strength. Light scattering/size exclusion chromatography showed complexes with two TrkC receptors per NT-3 dimer and one TrkC per heterodimer but did not detect binding of BDNF to TrkC. This latter result is not inconsistent with the sedimentation data, because the weak binding of BDNF to TrkC may be easily dissociated by nonspecific interactions of BDNF with the size exclusion column. The relative binding constants for these neurotrophins and the soluble receptor extracellular domains, as determined by sedimentation equilibrium, are correlated with their biological activity. However, the magnitude of these binding constants is insufficient by approximately 3 orders of magnitude to promote receptor dimerization at physiologically active concentrations.

Animals↗
PubMed1996

TrkA, but not TrkC, receptors are essential for survival of sympathetic neurons in vivo.

Neurotrophins and their signaling receptors, the Trk family of protein tyrosine kinases, play a major role in the development of the mammalian nervous system. To determine the precise stages that require Trk receptor signaling during development of the sympathetic system, we have analyzed the superior cervical ganglion (SCG) of embryonic and postnatal mice defective for each of the known Trk receptors. Transcripts encoding TrkC are detected in early sympathetic development, before the coalescence of the SCG. trkA expression appears at E13.5, becoming robust from E15.5 onward. In contrast, trkC expression decreases significantly after E15.5 and remains detectable only in a small subpopulation of cells. No significant trkB expression could be detected in the SCG at any developmental stage. Ablation of TrkA receptors does not affect neurogenesis, expression of neuronal markers, or initial axonal growth. However, these receptors are absolutely necessary for the survival of sympathetic neurons after E15.5 and for proper innervation of their distal targets. In contrast, mice defective for either TrkC or TrkB tyrosine kinase receptors do not display detectable defects in their SCGs. These results illustrate the differential roles of the Trk family of receptors during SCG development and define a critical role for TrkA signaling in the survival, but not differentiation, of SCG neurons. Moreover, these observations raise the possibility that at least some SCG neurons become neurotrophin-dependent before complete target innervation.

Animals↗