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Query: UNIPROT:P06889 (Mol)
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Expression of mRNAs for the protein tyrosine kinases trk, trkB and trkC, encoding essential components of high-affinity neurotrophin receptors, was studied in the spinal cord and dorsal root ganglion during normal development and in the adult rat following peripheral and central axon injury. Northern blots revealed multiple trkB transcripts in the embryonic, early postnatal and adult spinal cord with different patterns of expression during development. The levels of 9.0 kb and 4.8 kb trkB transcripts, encoding a full-length trkB receptor, increased progressively during embryonic development with maximal levels around birth, followed by a decline at adulthood. In contrast, the level of 7.5/7.0 kb trkB transcripts, encoding a truncated trkB receptor, reached maximal levels shortly after birth and similar levels remained in the adult animal. In the spinal cord a 4.7kb trkC transcript was detected with maximal levels shortly after birth. In situ hybridization revealed a uniform labeling throughout the spinal cord for both trkB and trkC mRNAs with maximal intensities of labeling shortly after birth. The level of the 2.4 kb trkB transcript in the spinal cord increased 5-fold 8 days after a crush lesion of the sciatic nerve or the dorsal root, while no change was seen in the levels of the other trkB transcripts. No change in the 4.7 kb trkC mRNA was seen following these two injuries, although increased levels of several smaller size trkC transcripts were observed. For both trkB and trkC, similar size transcripts as seen in the spinal cord were also detected in adult rat dorsal root ganglia. Consistent with previous observations of decreased levels of cytoskeletal proteins after peripheral and central axotomy, the level of neurofilment light chain mRNA decreased markedly in the dorsal root ganglia following a crush lesion of the sciatic nerve or of the dorsal root. A small decrease was also seen in the level of preprotachykinin-A mRNA encoding the protein precursor of substance P. In the same animals, the levels of all five trkB transcripts increased 3-fold in the dorsal root ganglia in response to these two injuries. A small increase was also seen in the level of trkC mRNA. The level of brain-derived neurotrophic factor (BDNF) mRNA increased two-fold in the dorsal root ganglia following either of the two lesions, while no change was detected in trk mRNA following these two injuries.(ABSTRACT TRUNCATED AT 400 WORDS)
Brain Res Mol Brain Res 1993 Mar
PMID:Expression of mRNAs for neurotrophin receptors in the dorsal root ganglion and spinal cord during development and following peripheral or central axotomy. 851 Apr 96

Neurotrophins are profound regulators of neuronal survival in the developing peripheral nervous system and are synthesized by peripheral neurons themselves both during development and in maturity. Neuronal neurotrophin expression may be importantly related to survival of mature neurons, both in normal and pathological states. We show here that brain-derived neurotrophic factor (BDNF) gene expression in dorsal root ganglia is strongly stimulated in vivo by another neurotrophin, nerve growth factor (NGF). Furthermore, colocalization studies show that many BDNF-expressing sensory neurons also express trk A, the high-affinity NGF receptor. These results demonstrate a novel regulatory mechanism for neurotrophin gene expression and suggest a paracrine function for neurotrophins in mature animals.
Mol Cell Neurosci 1996 Feb
PMID:Nerve growth factor regulates the expression of brain-derived neurotrophic factor mRNA in the peripheral nervous system. 873 81

Rapid advances in characterization of the biological actions mediated by the third member of the neurotrophin family, neurotrophin-3 (NT-3), have been made recently in vitro as well as in situ. These have been made possible by the cloning of the genes for NT-3 and for its transducing receptor tyrosine kinase TrkC. This article will focus on the roles of NT-3 in the nervous system. In situ localization of NT-3 consistent with that of its receptor is manifested at all developmental stages studied and into adulthood. Through TrkC, NT-3 signals a number of trophic effects, ranging from mitogenesis, promotion of survival, or differentiation, depending on the developmental stage of the target cells. The sites of action of NT-3 reside primarily in the peripheral nervous system (PNS), various areas of the central nervous system (CNS), and in the enteric system (ENS). Analyses of the phenotypes of transgenic mice lacking NT-3 or injection of embryos with a blocking antibody have so far revealed the essential role of NT-3 in development of specific populations of the PNS, and in particular of proprioceptive, nodose, and auditory sensory neurons and of sympathetic neurons. The actions of NT-3 also extend to modulation of transmitter release at several types of synapses in the periphery as well as in the adult CNS. In addition, NT-3 may play a role in the development of tissues other than the nervous system, such as the cardiovascular system. Future investigations will widen the understanding of the many roles of NT-3 on both neuronal and nonneuronal cells.
Mol Neurobiol 1996 Feb
PMID:Neurotrophin-3 as an essential signal for the developing nervous system. 873 39

The presence of mRNAs to the high affinity tyrosine kinase (Trk) receptors for neurotrophins was studied in visceral afferent neurons of the nodose and petrosal ganglia of adult and neonatal rats using in situ hybridization histochemistry. Neurons containing TrkA mRNA were found in the adult nodose and petrosal ganglia. About 10% of nodose ganglion neurons and 38% of petrosal ganglion neurons contained TrkA mRNA. The nodose and petrosal ganglia from 1 day old neonates also expressed TrkA mRNA. No TrkB mRNA-containing neurons were detected in the adult nodose and petrosal ganglia, whereas TrkB mRNA was detected in 1 day old neonatal nodose and petrosal ganglia. TrkC mRNA was found in about 9% of nodose ganglion neurons and 11% of petrosal ganglion neurons of adult rats. Likewise, low but detectable levels of TrkC mRNA were seen in 1 day old neonatal nodose and petrosal ganglia. These data demonstrate the presence of TrkA and TrkC in the adult nodose and petrosal ganglia and provide a substrate for the ongoing neurotrophin-induced regulation of these placodally derived visceral afferent neurons. The altered expression of Trk receptor mRNAs in the nodose and petrosal ganglia between the adult and neonatal rats may reflect developmentally regulated changes in neurotrophin responsiveness.
Brain Res Mol Brain Res 1996 May
PMID:Presence and localization of neurotrophin receptor tyrosine kinase (TrkA, TrkB, TrkC) mRNAs in visceral afferent neurons of the nodose and petrosal ganglia. 873 68

The POU-domain transcription factor Oct-2 is expressed in both B lymphocytes and sensory neurones, where its expression is regulated by nerve growth factor (NGF). In order to define a possible role for Oct-2 in neurotrophin signalling, we examined the expression of an NGF-regulated channel (capsaicin-evoked ion fluxes), neuropeptides (substance P, calcitonin gene-related peptide), structural proteins (neurofilaments and peripherin) and receptors (trks) in dorsal root ganglion neurones derived from perinatal transgenic mice containing a defective Oct-2 structural gene. Northern blots show that central nervous tissue contains a larger than normal (> 10 kb) mRNA transcript corresponding in size to an Oct-2 transcript encoding a defective protein. PCR analysis shows the absence of normal Oct-2 transcripts in dorsal root ganglia. In null mutants, capsaicin sensitivity, and neuropeptide and cytoskeletal protein expression were unaffected by the loss of Oct-2 expression. The number of sensory neurones and the gross morphology of CNS tissues that normally express high levels of Oct-2 were also examined and found to be normal in the null mutant. Heterozygous animals show normal thresholds of sensitivity to noxious heat and normal inflammatory responses. Oct-2 does not therefore play an essential role in the NGF responsiveness of sensory neurones in these animals.
Brain Res Mol Brain Res 1995 Nov
PMID:Nerve growth factor-regulated properties of sensory neurones in Oct-2 null mutant mice. 875 Aug 82

Recently we reported that human recombinant acidic fibroblast growth factor (aFGF) is capable of preventing degeneration of nucleus basalis magnocellularis neurons in vivo and inducing growth of astrocytes in vitro. In the present study, the effects of aFGF on the concentration of nerve growth factor (NGF) and its messenger RNA were investigated in the rat cerebral cortex following unilateral cortical infarction. Lesioned animals exhibited a significant increase of NGF in the remaining cortex ipsilateral to the lesion. After combining cortical lesion with intracerebroventricular application of aFGF (12 micrograms/day for 7 days), we observed an 8-fold increase in the NGF concentration and a marked increase in the level of steady state NGF mRNA relative to controls ipsilaterally, and a less pronounced aFGF effect in the contralateral cerebral cortex. These results support the hypothesis that the neurotrophic effects previously shown for aFGF and basic FGF (bFGF) in neurotrophin-sensitive neurons is mediated by inducing increased production of NGF within the injured central nervous system (CNS) of adult animals.
Brain Res Mol Brain Res 1995 Oct
PMID:Acidic FGF induces NGF and its mRNA in the injured neocortex of adult animals. 877 40

Neurotrophins regulate neuronal survival and phenotypic differentiation. Recent evidence also suggests a role in the modulation of synaptic activity. Using neuronal cell cultures from embryonic hippocampus, we previously found that application of brain-derived neurotrophic factor rapidly enhanced synaptic transmission. We now report that application of neurotrophin-4, another ligand for the trkB neurotrophin receptor, was equally effective in enhancing synaptic currents. In contrast, nerve growth factor, neurotrophin-3, basic fibroblast growth factor and epidermal growth factor did not share this action. Our results suggest that activation of trkB receptors plays a selective role in the regulation of synaptic efficacy in the hippocampus.
Brain Res Mol Brain Res 1996 Jun
PMID:Selective role for trkB neurotrophin receptors in rapid modulation of hippocampal synaptic transmission. 879 19

Receptor tyrosine kinases (RTKs) play important roles in cellular differentiation, survival, and proliferation. To search for genes involved in the survival of motoneurons, we isolated the RTKs specifically expressed on them. We used RT-PCR, by which RNA was obtained from purified embryonic day 5 (E5) chick motoneurons, and screened by in situ hybridization. Of 17 RTK cDNA clones, c-ret expression gradually increased in the motoneurons of the spinal cord during development. Compared with the expression of the neurotrophin receptor, TrkC, that of c-ret was very high in motoneurons from around E17 to adulthood. The level of c-ret expression on the motoneurons was unaffected by deafferentation at E2, but changed after denervation at post-hatching day 2. The in situ hybridization signal for c-ret mRNA increased slightly at day 1, then decreased progressively up to day 8, and increased again 2 weeks after sciatic nerve denervation in the motoneurons of the lumbar spinal cord. There were also changes in the signal of the lesioned sciatic nerve. In the most distal part from the lesioned site, the signal for c-ret mRNA significantly increased from day 3 on after denervation. These results suggested that the c-ret gene may encode the receptor for a factor involved in motoneuron differentiation and the promotion of regeneration of injured peripheral nerves.
Brain Res Mol Brain Res 1996 Jul
PMID:Developmental and denervation changes in c-ret proto-oncogene expression in chick motoneurons. 880 8

We have investigated the role(s) of conserved sequences in the extracellular domain of rat trkA by generating 5' and 3' deletions and assaying changes in neurotrophin binding, tyrosine kinase activity, and neurite outgrowth. Essential sequences required for both nerve growth factor (NGF) and neurotrophin-3 (NT-3) binding were mapped to the immunoglobulin-like domains. Small deletions in the second immunoglobulin-like domain and in the juxtamembrane region abolished neurotrophin binding. Dose-response curves on cells expressing full-length trkA were identical for NGF and NT-3 (0.1 ng/ml-50 ng/ml) while cells expressing leucine rich motif (LRM) minus receptors required high concentrations of NT-3 (50 ng/ml). Scatchard analysis revealed a loss of high-affinity NT-3, but not NGF, binding to the LRM minus receptor consistent with the neurite dose-response curves. Moreover, cells expressing the LRM minus receptors failed to fasciculate and showed delayed arborization in comparison to cells expressing wild-type trkA, suggesting a possible role for the LRM's in neurotrophin-induced differentiation and in high-affinity NT-3 binding.
Mol Cell Neurosci 1996 May
PMID:Deletions in the extracellular domain of rat trkA lead to an altered differentiative phenotype in neurotrophin responsive cells. 881 63

To determine critical periods of action, the effects of trophic factors on rat lumbar dorsal root ganglion (DRG) neurons were evaluated during neurogenesis, and after neurogenesis, before and after target contact. Brain-derived neurotrophic factor and neurotrophin-4 increased E12.5 DRG neuronal survival. Leukemia inhibitory factor enhanced neuronal differentiation. NGF and NT3 increased BrdU incorporation in neurons derived from E12.5 DRG neuroblasts. By contrasts, neurotrophin dependence switched at E14.5 such that BDNF had no survival activity but NGF, NT3, and NT4 supported survival of the same neurons. At birth, DRG neurons were supported by NGF and to a lesser extent, leukemia inhibitory factor. Thus, specific trophic factors discretely regulate proliferation, differentiation, and survival in DRG at different ages. This study complements genetic studies of neurotrophin and trk activity by identifying the critical period of action for and the specific events regulated by each neurotrophin.
Mol Cell Neurosci 1995 Aug
PMID:Proliferation, differentiation, and survival of rat sensory neuron precursors in vitro require specific trophic factors. 884 2


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