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PubMed1999

Fusion of ETV6 to neurotrophin-3 receptor TRKC in acute myeloid leukemia with t(12;15)(p13;q25).

Chromosome translocations involving band 12p13 are known to be involved in a variety of hematologic malignancies, some of them resulting in rearrangement of the ETV6/TEL gene. Applying the fluorescence in situ hybridization (FISH) method, we found a cryptic translocation t(12;15)(p13;q25) in an adult acute myeloid leukemia (AML) patient. Hybridization with cosmid probes showed that the ETV6 gene was rearranged in this translocation. A patient-specific cDNA library was screened with ETV6 cDNA, and a novel fusion transcript was identified between the ETV6 and TRKC/NTRK3 gene located on 15q25. TRKC is a receptor tyrosine kinase that is activated by neurotrophin-3 (NT-3). It is known to be expressed broadly in neural tissues but not in hematologic cells, so far. ETV6-TRKC chimeric transcript encoded the pointed (PNT) domain of the ETV6 gene that fused to the protein-tyrosine kinase (PTK) domain of the TRKC gene. Two types of fusion transcript were determined, one that included the entire PTK domain of TRKC and the other in which the 3'-terminal 462 bp of TRKC was truncated within the PTK domain. Western blot analysis showed the expression of both chimeric proteins of 52 and 38 kD in size. Our results suggest that chimeric PTK expressed in the leukemic cells may contribute to cellular transformation by abnormally activating TRK signaling pathways. Moreover, this is the first report on truncated neurotrophin receptors associated in leukemia.

Acute Disease↗

PubMed1997

The trkC receptor is transiently localized to Purkinje cell dendrites during outgrowth and maturation in the rat.

In vivo studies of granule cell gene expression during corticocerebellar development and in vitro studies of Purkinje cell neurite outgrowth suggest that neurotrophin-3 may influence growth of Purkinje cell dendrites. To determine whether neurotrophic substances affect the growth of specific neuronal processes (i.e. axons and dendrites) or nonspecifically cause process development by exerting a trophic influence upon neuronal physiology we performed an immunohistochemical examination of trkC protein expression during early postnatal development of the rat cerebellum. Our findings indicate that Purkinje cells begin to synthesize trkC protein coincident with the onset of dendritic outgrowth. Robust immunostaining was evident throughout the entire somatodendritic domain of Purkinje cells during dendritic development but became faint and restricted to the cell body subsequent to the completion of dendritogenesis. These results suggest that growth and maturation of the Purkinje cell dendritic arbor may be influenced by neurotrophin-3 activation of trkC receptors distributed within developing dendrites.

Animals↗

PubMed2005

The neurotrophin-3 receptor TrkC directly phosphorylates and activates the nucleotide exchange factor Dbs to enhance Schwann cell migration.

During the development of the peripheral nervous system, Schwann cells, the myelin-forming glia, migrate along axons before initiating myelination. We previously demonstrated that endogenous neurotrophin-3 (NT3) acting through the TrkC tyrosine kinase receptor enhances migration of premyelinating Schwann cells. This signaling pathway is mediated by the c-Jun N-terminal kinase (JNK) cascade regulated by the Rho GTPases Rac1 and Cdc42. However, missing is the link between TrkC and the GTPases. Here, we show that a guanine-nucleotide exchange factor (GEF), Dbl's big sister (Dbs), couples with TrkC to activate Cdc42 in Schwann cells. Furthermore, TrkC directly phosphorylates Dbs, thereby inducing the Cdc42-GEF activity. Taken together, activation of TrkC triggers Schwann cell migration by regulating Dbs upon direct tyrosine phosphorylation, providing a mechanism whereby a membrane receptor tyrosine kinase can induce the activation of Rho GTPase-GEFs.

Animals↗

PubMed1994

The binding epitopes of neurotrophin-3 to its receptors trkC and gp75 and the design of a multifunctional human neurotrophin.

Survival and maintenance of vertebrate neurons are influenced by neurotrophic factors which mediate their signal by binding to specific cell surface receptors. We determined the binding sites of human neurotrophin-3 (NT-3) to its receptors trkC and gp75 by mutational analysis and compared them to the analogous interactions of nerve growth factor (NGF) with trkA and gp75. The trkC binding site extends around the central beta-strand bundle and in contrast to NGF does not make use of non-conserved loops and the six N-terminal residues. The gp75 epitope is dominated by loop residues and the C-terminus of NT-3. A novel rapid biological screening procedure allowed the identification of NT-3 mutants that are able to signal efficiently through the non-preferred receptors trkA and trkB, which are specific for NGF and BDNF respectively. Mutation of only seven residues in NT-3 resulted in a human neurotrophin variant which bound to all receptors of the trk family with high affinity and efficiently supported the survival of NGF-, BDNF- and NT-3-dependent neurons. Our results suggest that the specificity among neurotrophic factors is not solely encoded in sequence diversity, but rather in the way each neurotrophin interacts with its preferred receptor.

Amino Acid Sequence↗

PubMed2001

Dimeric beta-turn peptidomimetics as ligands for the neurotrophin receptor TrkC.

Twelve dimeric peptidomimetics 1 were prepared via a divergent-convergent strategy. These peptidomimetics incorporated the same amino acids as i +1 and i + 2 residues in key beta-turns of the neurotrophin NT-3. Cytosensor microphysiometry was used to gauge the effects of the dimers 1 on cells that overexpress the NT-3 receptor, TrkC. Increases in extracellular acidification rates were observed for some monomers 3, but the active dimers gave greater effects.

Cell Line↗

PubMed1994

Expression of the neurotrophin receptor TrkC is linked to a favorable outcome in medulloblastoma.

Medulloblastoma, the most common malignant brain tumor of childhood, has a variable prognosis. Although half of the children and young adults with the disease survive longer than 10 years after diagnosis, the others relapse and die despite identical therapy. We have examined the expression of neurotrophins and their receptors in medulloblastoma samples snap frozen in the operating room to preserve RNA integrity. All tumors (n = 12) were found to express mRNA encoding neurotrophin 3 and its receptor TrkC. The level of trkC expression was highly variable, with a more than 50-fold difference between the highest and lowest values. By Kaplan-Meier analysis, patients with tumors expressing high levels of trkC mRNA had significantly longer intervals without disease progression than those with low levels (log-rank, P = 0.03) and a more favorable overall survival (log-rank, P = 0.05). Thus, trkC expression is a prognostic indicator for patients with medulloblastoma.

Brain-Derived Neurotrophic Factor↗

PubMed2006

Dok5 is substrate of TrkB and TrkC receptors and involved in neurotrophin induced MAPK activation.

Tropomyosin-related kinase (Trk) family receptors are a group of high affinity receptors for neurotrophin growth factors, which have pivotal functions in many physiological processes of nervous system. Trk receptors can dimerize and autophosphorylate upon neurotrophin stimulation, then recruit multiple adaptor proteins to transduct signal. In this report, we identified Dok5, a member of Dok family, as a new substrate of TrkB/C receptors. In yeast two-hybrid assay, Dok5 can interact with intracellular domain of TrkB and TrkC receptor through its PTB domain, but not with that of TrkA receptor. The interaction was then confirmed by GST pull-down assay and Co-IP experiment. Dok5 co-localized with TrkB and TrkC in differentiated PC12 cells, providing another evidence for their interaction. By using mutational analysis, we characterized that Dok5 PTB domain bound to Trk receptor NPQY motif in a kinase-activity-dependent manner. Furthermore, competition experiment indicated that Dok5 competed with N-shc for binding to the receptors at the same site. Finally, we showed that Dok5 was involved in the activation of MAPK pathway induced by neurotrophin stimulation. Taken together, these results suggest that Dok5 acts as substrate of TrkB/C receptors and is involved in neurotrophin induced MAPK signal pathway activation.

Adaptor Proteins, Signal Transducing↗

PubMed2001

Adenovirus vector-directed expression of the neurotrophin-3 receptor (TrkC) in mouse astrocytes.

In the present article we report the generation of a neurovirological reagent, an adenovirus vector that efficiently delivers the gene for the Neurotrophin-3 (NT-3) receptor, TrkC. Using this AdTrkC vector, we examined the induction of the expression of the above neurotrophin receptor in pure cultures of mouse astrocytes, a glial cell type that does not constitutively express this gene. Infection of astrocytes at an optimal dose of 100-200 plaque forming units (p.f.u.) per cell, induced expression of specific mRNA, as demonstrated by RT-PCR and Northern blot. This mRNA was translated to produce a mean of 20,157 biologically active receptor molecules per astrocyte with a Kd of 4.1 x 10(-11) M, as demonstrated by 125I-NT-3 binding. After 2D electrophoresis, the mature glycoprotein and some precursors were recognised by antibodies raised against the carboxy-terminal peptide of Trk. Binding of the ligand induced autophosphorylation ofTrkC and 3H-thymidine incorporation in transduced cells. These results demonstrate that our AdTrkC vector efficiently mediates the expression of high-levels of biologically active NT-3 receptors.

Adenoviridae↗

PubMed2006

Quantitative mRNA expression analysis of neurotrophin-receptor TrkC and oncogene c-MYC from formalin-fixed, paraffin-embedded primitive neuroectodermal tumor samples.

Most recent studies analyzing candidate biological prognostic factors (including neurotrophin receptor TrkC and proto-oncogene c-MYC) in childhood primitive neuroectodermal brain tumors (PNET) are limited by small patient numbers due to dependence on fresh-frozen tumor material. In contrast, large archives of formalin-fixed, paraffin-embedded PNET samples exist from homogeneously treated patients. The ability of real-time RT-PCR to assay very small mRNA fragments makes this assay amenable to studies where the RNA is moderately or even highly degraded. We have optimized RNA isolation from archive PNET samples and found that TrkC and c-MYC mRNA measurements significantly correlated with those obtained from matching fresh-frozen tissues. Exploitation of already existing archives of formalin-fixed paraffin-embedded PNET samples may accelerate the building of better stratification systems for PNET patients.

Adolescent↗

PubMed1996

Inhibition of the NT-3 receptor TrkC, early in chick embryogenesis, results in severe reductions in multiple neuronal subpopulations in the dorsal root ganglia.

To assess functions of neurotrophins at defined times in development, we have prepared antibodies of the extracellular domains of each of the trk receptors. Here, antibodies to trkC, the major receptor for NT-3, are used to examine trkC expression and function during the formation and maturation of the chick dorsal root ganglion (DRG). Our results show that in the immature DRG, the majority of cells express trkC, and inhibition of trkC activation results in reductions in neuronal numbers before the period of target-mediated cell death, the time when neurotrophins previously have been shown to regulate survival. Furthermore, blockade of trkC in ovo induced reductions in subpopulations of DRG neurons known to be dependent on NGF, in addition to those dependent on NT-3 during the target-regulated cell death period. An early function for NT-3 on immature DRG neurons is supported further by data presented here that demonstrate that whereas BDNF and NGF can support a subset of immature DRG neurons in vitro, activation of the trkC receptor either by NT-3 binding or via antibody-mediated cross-linking induces the most robust survival response. When all three neurotrophins are combined, the number of surviving neurons does not exceed that supported by NT-3 alone. Together, these data are consistent with coexpression of more than one trk receptor family member on immature sensory neurons, and they demonstrate that inhibition of trkC activation has surprisingly early and pleiotrophic effects on the development of spinal sensory ganglia.

Animals↗

PubMed2006

Transgenic mice overexpressing the full-length neurotrophin receptor TrkC exhibit increased catecholaminergic neuron density in specific brain areas and increased anxiety-like behavior and panic reaction.

Accumulating evidence has suggested that neurotrophins participate in the pathophysiology of mood disorders. We have developed transgenic mice overexpressing the full-length neurotrophin-3 receptor TrkC (TgNTRK3) in the central nervous system. TgNTRK3 mice show increased anxiety-like behavior and enhancement of panic reaction in the mouse defense test battery, along with an increase in the number and density of catecholaminergic (tyrosine hydroxylase positive) neurons in locus coeruleus and substantia nigra. Furthermore, treatment of TgNTRK3 mice with diazepam significantly attenuated the anxiety-like behaviors in the plus maze. These results provide evidence for the involvement of TrkC in the development of noradrenergic neurons in the central nervous system with consequences on anxiety-like behavior and panic reaction. Thus, changes in TrkC expression levels could contribute to the phenotypic expression of panic disorder through a trophic effect on noradrenergic neurons in the locus coeruleus. Our results demonstrate that the elevated NT3-TrkC tone via overexpression of TrkC in the brain may constitute a molecular mechanism for the expression of anxiety and anxiety.

Animals↗

PubMedDate not supplied

Neurotrophin receptor TrkC predicts good clinical outcome in medulloblastoma and other primitive neuroectodermal brain tumors.

BACKGROUND: Neurotrophins and their cognate receptors TrkA, TrkB and TrkC regulate proliferation, differentiation and death of neuronal progenitor cells and may be implicated in the progression of medulloblastoma and other primitive neuroectodermal brain tumors (PNET). These common childhood brain tumors are composed of morphologically undifferentiated cells that have important similarities to neuroectodermal progenitor cells of the developing CNS. PATIENTS AND METHODS: To identify biologic prognostic factors in childhood PNET we determined expression levels of TrkC mRNA in tumor samples from 87 PNET patients by in situ hybridization. Comparison of TrkC mRNA expression levels with clinical variables was performed using univariate and multivariable Cox regression analysis. RESULTS: Cox regression analysis revealed that children with tumors expressing no or little TrkC mRNA had a 4.8-fold (p < 0.00005) greater risk of death than children with tumors with high TrkC mRNA expression. This hazard ratio remained consistent after adjusting for clinical variables. Five-year survival was 89% for patients with PNETs expressing high levels of TrkC mRNA and 47% for patients with PNETs expressing little or no levels of TrkC mRNA (log rank; p < 0.00005). CONCLUSIONS: The TrkC neurotrophin receptor appears to be a powerful independent prognostic factor in PNET and may have a role in patient assignment to risk-based treatment strategies.

Adolescent↗

PubMed1994

Expression of trkC receptor mRNA during development of the avian nervous system.

Neurotrophin-3 (NT-3) has mitogenic and neurogenic activities on distinct central and peripheral nervous system (CNS and PNS) progenitors in avian embryos. It was therefore important to characterize in detail the expression pattern of TrkC, a high-affinity receptor for NT-3, during nervous system ontogeny. We report that trkC-encoding transcripts are expressed in the CNS primordium in several spatiotemporal distinct waves. trkC mRNA becomes evident in the dividing neuroepithelium where it is expressed homogeneously. A subsequent enhancement of the signal in dorsal areas of the neural tube occurs concomitant with the migration of neural crest cells from the CNS. Expression of trkC mRNA is then reduced in the germinal epithelium while progressively appearing on postmitotic neurons at the periphery of the neural tube. At a time preceeding the onset of normal motoneuron death, trkC signal is transiently undetectable in the ventral third of the neural tube. Diffuse expression in the spinal cord is resumed on embryonic day (E) 7. Subsets of premigratory and migrating neural crest progenitors also express the trkC receptor. Intense trkC signal is then evident throughout the newly organizing dorsal root ganglia (DRG), and becomes later restricted to defined postmitotic neuronal populations. Cranial ganglia also express the trkC gene from early stages of gangliogenesis. Furthermore, whereas the primary sympathetic ganglia show trkC mRNA, in the secondary ganglia a barely detectable signal could be observed. The dynamic up- and down-regulations of trkC reported here to occur both in the CNS and PNS primordia correspond to diverse, though only partially known, developmental processes. Taken together, these results support the notion that the NT-3-TrkC complex mediates diverse functions during neural development.

Animals↗

PubMed1995

Co-expression of TrkB and TrkC receptors in CNS neurones suggests regulation by multiple neurotrophins.

Using double-label in situ hybridization, we have explored the possibility that individual CNS neurones can co-express mRNAs for the high-affinity receptors of brain-derived neurotrophic factor and neurotrophin-3, TrkB and TrkC, respectively. The vast majority of TrkC mRNA-containing neurones in the hippocampal formation and cerebral cortex were also labelled for TrkB mRNA. Cells expressing only TrkB or TrkC mRNA were very scarce in these regions, representing < 15% of all labelled cells. These findings suggest that the same cortical or hippocampal neurone can be regulated by several members of the neurotrophin family, which may be important both during development and in response to physiological activity and pathological conditions.

Animals↗

PubMed1996

Neurotrophin-3 increases intracellular calcium in a rat insulin-secreting cell line through its action on a functional TrkC receptor.

Pancreatic beta cells and neuronal cells show a large number of similarities. For example, functional receptors for nerve growth factor are present in beta cells. Here we investigate whether TrkC, a neuronal high affinity receptor for neurotrophin-3, is expressed in the insulin-secreting cell line INS-1. We demonstrate the expression in INS-1 cells of mRNAs coding for TrkC identical in size to those found in the brain. As in neuronal cells, different alternatively spliced forms of TrkC mRNA, differing by the insertion of an alternative exon in their kinase domain, were expressed in INS-1 cells. TrkC protein is also expressed in INS-1 cells and is functional. Indeed, when INS-1 cells were treated with neurotrophin-3, TrkC became phosphorylated on tyrosine residues, and the expression of early response genes was induced. This activation of the receptor was paralleled by a rapid and transient increase in cytosolic free calcium due to an influx of extracellular calcium. Functional receptors for NT-3 are thus expressed in INS-1 cells. This cell line provides a new model for the study of NT-3 signal transduction and should be useful in the understanding of the role of neurotrophins in insulin-secreting cells.

Amino Acid Sequence↗

PubMed2003

Neurotrophin 3 and its receptor TrkC immunoreactivity in glucagon cells of buffalo pancreas.

Neurotrophin 3 (NT3), a member of the neurotrophin family, and its specific receptor tyrosine kinase C (TrkC) are involved in the differentiation, survival, and maintenance of many neuronal populations. Recently, NT3 and TrkC were also retained involved in the biology of non-neuronal tissues. In this study, we report the presence of NT3- and TrkC-immunoreactive cells in the endocrine pancreas of adult buffalos. They were usually distributed at the periphery of islets and showed intense immunoreactivity. By double immunohistochemical staining, NT3- and TrkC-IR resulted to be colocalized in glucagon immunoreactive cells. These findings suggest endocrine and/or autocrine roles of NT3 in pancreatic A cells.

Age Factors↗

PubMed1998

NT-3-mediated TrkC receptor activation promotes proliferation and cell survival of rodent progenitor oligodendrocyte cells in vitro and in vivo.

We have previously described the expression of a functional full-length trkC transcript for neurotrophin-3 (NT-3) receptor in oligodendroglia (OL) cells (Kumar and de Vellis, 1996). To date, the role of NT-3 and its signal transduction cascade in OL remains poorly defined. We report that the NT-3 responsive population of cells in the OL lineage are the progenitor cells and that the addition of NT-3 results in the autophosphorylation of p145TrkC. Furthermore, NT-3-mediated activation of p21ras and mitogen-activated protein kinase (MAPK), extracellular signal-regulated protein kinase2 (ERK2), were also observed in the progenitor OL cells. These protein tyrosine kinase (PTK)-induced responses were sensitive to the presence of K252a, an inhibitor for tyrosine kinase. We have determined that NT-3 promotes progenitor OL cell commitment to enter into S-phase of cell cycle to initiate DNA synthesis, in a manner similar to platelet-derived growth factor-AA (PDGF-AA). NT-3 thus plays a role in cell proliferation when present alone, while augmenting the proliferation capacity of PDGF-AA as indicated by the nuclear binding activity of the transcription factor, E2F-1. Both the initiation and progression of mitotic events were confirmed by the expression of c-myc and cdc2 in the presence of NT-3, PDGF-AA or NT-3 plus PDGF-AA. A cell survival assay examining interleukin 1-beta-converting enzyme (ICE)-like protease-mediated cleavage of poly (ADP-ribose) polymerase (PARP) revealed an increase in OL progenitor cell death in the absence of NT-3 or PDGF-AA. In corroboration with our in vitro studies, in vivo results show an increased expression of the progenitor OL cell marker, glycerol phosphate dehydrogenase (GPDH) within 48 hr following an intracranial injection of NT-3, PDGF-AA, or NT-3 plus PDGF-AA in PN4-5 rats. These novel findings suggest that PDGF-AA potentiates the OL progenitor cell's ability to enter into the S-phase of the cell cycle and that NT-3 can augment this activity. Furthermore, PDGF-AA and NT-3 can block ICE-like protease-mediated PARP fragmentation in progenitor OL cells. These results provide important information which further delineates the signal transduction cascades and the role of NT-3 and PDGF-AA on OL progenitor cells.

Animals↗

PubMed2004

Changes in retinal expression of neurotrophins and neurotrophin receptors induced by ocular hypertension.

Open angle glaucoma is defined as a progressive and time-dependent death of retinal ganglion cells concomitant with high intraocular pressure, leading to loss of visual field. Because neurotrophins are a family of growth factors that support neuronal survival, we hypothesized that quantitative and qualitative changes in neurotrophins or their receptors may take place early in ocular hypertension, preceding extensive cell death and clinical features of glaucoma. We present molecular, biochemical, and phenotypic evidence that significant neurotrophic changes occur in retina, which correlate temporally with retinal ganglion cell death. After 7 days of ocular hypertension there is a transient up-regulation of retinal NGF, while its receptor TrkA is up-regulated in a sustained fashion in retinal neurons. After 28 days of ocular hypertension there is sustained up-regulation of retinal BDNF, but its receptor TrkB remains unchanged. Throughout, NT-3 levels remain unchanged but there is an early and sustained increase of its receptor TrkC in Müller cells but not in retinal ganglion cells. These newly synthesized glial TrkC receptors are truncated, kinase-dead isoforms. Expression of retinal p75 also increases late at day 28. Asymmetric up-regulation of neurotrophins and neurotrophin receptors may preclude efficient neurotrophic rescue of RGCs from apoptosis. A possible rationale for therapeutic intervention with Trk receptor agonists and p75 receptor antagonists is proposed.

Animals↗