Abstract. The neurotrophin family includes NGF, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4). Previous studies have demonstrated that expression of NGF and its low-affinity receptor is induced in nonneuronal cells of the distal segment of the transected sciatic nerve suggesting a role for NGF during axonal regeneration (Johnson, E. M., M. Taniuchi, and P. S. DeStefano. 1988. Trends Neurosci. 11:299-304). To assess the role of the other neurotrophins and the members of the family of Trk signaling neurotrophin receptors, we have here quantified the levels of mRNAs for BDNF, NT-3, and NT-4 as well as mRNAs for trkA, trkB, and trkC at different times after transection of the sciatic nerve in adult rats. A marked increase of BDNF and NT-4 mRNAs in the distal segment of the sciatic nerve was seen 2 wk after the lesion. The increase in BDNF mRNA was mediated by a selective activation of the BDNF exon IV promoter and adrenalectomy attenuated this increase by 50%. NT-3 mRNA, on the other hand, decreased shortly after the transection but returned to control levels 2 wk later. In Schwann Cells ensheathing the sciatic nerve, only trkB mRNA encoding truncated TrkB receptors was detected with reduced levels in the distal part of the lesioned nerve. Similar results were seen using a probe that detects all forms of trkC mRNA. In the denervated gastrocnemius muscle, the level of BDNF mRNA increased, NT-3 mRNA did not change, while NT-4 mRNA decreased. In the spinal cord, only small changes were seen in the levels of neurotrophin and trk mRNAs. These results show that expression of mRNAs for neurotrophins and their Trk receptors is differentially regulated after a peripheral nerve injury. Based on these results a model is presented for how the different neurotrophins could cooperate to promote regeneration of injured peripheral nerves.
In this study the actions of NGF in regulating peptide expression were examined in vivo in adult rat primary sensory neurons. The hypothesis that NGF might tonically inhibit expression of some peptides was tested specifically. In situ hybridization and immunohistochemistry were used to detect presence or absence of alpha-CGRP, beta-CGRP, SP, SOM, VIP, CCK, NPY, and GAL as well as their mRNAs. In neurons in normal lumbar DRG alpha-CGRP, beta-CGRP, SP, and SOM are abundantly and heterogeneously expressed whereas few neurons have detectable VIP, CCK, NPY, or GAL. Two weeks following sciatic nerve transection, concentrations of alpha-CGRP, beta-CGRP, SP, and SOM plus their mRNAs have decreased to background in all but a few neurons. In contrast, VIP, CCK, NPY, and GAL are now synthesized in many neurons. Delayed intrathecal infusion of NGF (125 ng/microliter/hr) for 7 d, starting 2 weeks after injury counteracted the decrease in expression of alpha- CGRP, beta-CGRP and SP expression, but not SOM. This lack of influence of NGF on SOM is consistent with the absence of high-affinity NGF receptors and trk mRNA in SOM-positive neurons. Delayed infusion of NGF also reduced the number of neurons expressing VIP, CCK, NPY, and GAL after injury by approximately one-half in each subpopulation. Therefore, we suggest that NGF suppresses expression of these four peptides but only if the neurons also have NGF receptors. The results show that NGF can regulate peptide expression differentially and may also be part of the signal that allows reversion to normal of responses to injury as axons regenerate.
The distributions of mRNAs for the protooncogene trk and the low- affinity NGF receptor (LNGFR) were studied by hybridization with oligonucleotide probes on sections of adult rat primary sensory and sympathetic ganglia. For comparison with high-affinity binding sites, adjacent sections were processed for NGF receptor radioautography. Among neurons in lumbar dorsal root ganglia and trigeminal ganglia, trk mRNA and NGF-binding sites were closely colocalized; this finding together with previous direct evidence in other cell types is taken to indicate that trk protein is an essential component of the high- affinity NGF receptor in adult sensory neurons. In lumbar dorsal root ganglia and trigeminal ganglia, abundant LNGFR mRNA was found in all neurons with strong 125I-NGF labeling and on additional neurons lacking high-affinity NGF-binding sites. The presence of abundant LNGFR in neurons with high-affinity receptors could be the cause and/or consequence of their ability to respond to NGF. Neurons with abundant LNGFR mRNA but few high-affinity NGF-binding sites may have receptors for other members of the neurotrophin family. In nodose ganglia, neurons with high concentrations of LNGFR mRNA greatly outnumbered the small percentage with abundant trk mRNA. Following intrathecal infusion of NGF to otherwise normal dorsal root ganglia, the concentrations of LNGFR mRNA but not those of trk mRNA and NGF-binding sites were increased in NGF-responsive neurons. The usual single normal pattern of frequency histograms of LNGFR labeling indices became bimodal in response to NGF. Concentrations of NGF-binding sites, LNGFR mRNA, and trk mRNA were all decreased by peripheral nerve transection and restored by exogenous NGF, the restoration being complete for LNGFR mRNA and partial for trk mRNA and NGF-binding sites. The data indicate that NGF can regulate both LNGFR and trk mRNAs but do not clarify the possible contribution of the LNGFR protein to high-affinity binding sites.
In the current study we examined the effects of training in adult rats with a cervical spinal cord injury (SCI). One group of rats received 6 weeks of training in a single pellet reaching task immediately after injury, while a second group did not receive training. Following this period changes in cortical levels of BDNF and GAP-43 were analysed in trained and untrained animals and in a group with training but no injury. In another group of rats, functional recovery was analysed in the reaching task and when walking on a horizontal ladder. Thereupon, the cortical forelimb area was electrophysiologically examined using micro-stimulation followed by tracing of the lesioned corticospinal tract (CST). We found that trained rats improved substantially in the reaching task, when compared to their untrained counterparts. Trained rats however, performed significantly worse with their injured forelimb when walking on a horizontal ladder. In parallel to the improved recovery in the trained task, we found that the cortical area where wrist movements could be evoked by micro-stimulation expanded in trained rats in comparison to both untrained and uninjured rats. Furthermore, collateral sprouting of lesioned CST fibres rostral to the injury was increased in trained rats. Post-injury training was also found to increase cortical levels of GAP-43 but not BDNF. In conclusion we show that training of a reaching task promotes recovery of the trained task following partial SCI by enhancing plasticity at various levels of the central nervous system (CNS), but may come at the cost of an untrained task.
With the immunofluorescence technique, nitric oxide synthase (NOS)-like immunoreactivity (LI) was found in a few medium-sized and small sensory neurons in lumbar (L) 4 and L5 dorsal root ganglia (DRG) of normal rat, and in most of these neurons, NOS-LI coexisted with calcitonin gene-related peptide and sometimes with substance P and galanin. NOS-immunoreactive nerve fibers, terminals and small neurons were also located in the dorsal horn of the segments 4 and 5 of the rat lumbar spinal cord with the highest density in inner lamina II. Many NOS-positive neurons and fibers were seen in the area around the central canal. A sparse network of NOS-immunoreactive nerve fibers was found in the ventral horn. After unilateral sciatic nerve cut in the rat, the number of NOS-positive neurons increased in the ipsilateral L4 and L5 DRGs, mainly in medium and small neurons, but also in some large neurons and very small neurons. NOS-LI could now also be seen in the ipsilateral dorsal roots, and in an increased number of fibers and terminals in both outer and inner lamina II of the ipsilateral dorsal horn. The number of NOS-immunoreactive neurons in lamina II of the ipsilateral dorsal horn was reduced. In the monkey L4 and L5 DRGs, many small neurons were NOS-immunoreactive, but only a few weakly stained nerve fibers and terminals were found in laminae I-IV of the dorsal horn at L4 and L5 lumbar levels. A few NOS-positive neurons were present in lamina X. The number of NOS-immunoreactive neurons was somewhat reduced in DRGs 14 days after peripheral axotomy, but no certain effect was seen in the dorsal horn. These results, together with earlier in situ hybridization studies, demonstrate that axotomy in rat induces a marked upregulation of NOS synthesis in primary sensory neurons, thus suggesting a role for NO in lesioned sensory neurons. In contrast, no such effect was recorded in monkey, perhaps indicating distinct species differences.
In situ hybridization on sections from the adult rat peripheral and central nervous systems demonstrated that trkB mRNA was expressed not only by neurons but also by cells in central nervous system white matter as well as by Schwann cells in the sciatic nerve. In situ hybridization with an oligonucleotide complementary to the trkB tyrosine kinase domain could only demonstrate mRNA in neurons, indicating expression of truncated trkB receptors lacking the tyrosine kinase domain by glial cells. RNA blot analysis was performed on separately cultured central nervous system glial cells to study which cell types express trkB mRNA. Several transcripts encoding truncated trkB receptors were expressed at high levels in 0-2A progenitors, astrocytes, and oligodendrocytes, but no trkB mRNA could be detected in microglia. The expression of trkB mRNA by glial cels in vivo was also investigated after inJury; strongly elevated levels of mRNA encoding truncated receptors were detected in the glial scar formed after an incision in the spinal cord dorsal funiculus. In contrast, in the cut sciatic nerve, trkB mRNA decreased distal to the transection, and by 3 weeks only very low levels of mRNA could be detected. Immunoelectron microscopy located trkBlike inmunoreactivity to axons and Schwann cells in the sciatic nerve. The expression of truncated trkB receptors by astrocytes, oligodendrocytes, and Schwann cells and the altered levels in response to inuury indicate that glial trkB receptors may serve an important function in the intact and injured nervous system.The first isolated and best characterized neurotrophic factor, nerve growth factor (NGF; ref. 1), is a member of a group of neurotrophic factors called the neurotrophin (NT) family. In addition to NGF this group of related molecules consists of brain-derived neurotrophic factor (BDNF; refs. 2 and 3), NT-3 (4-9), and NT-4 (10-12). The biological effects of the NTs are mediated by binding with high affinity to different, but closely related, cell surface glycoprotein receptors encoded by members of the trk family of protooncogenes. The first identified gene, trk, codes for gpl4Otrk, which is a receptor for NGF (13,14). The trkB gene encodes at least two glycoproteins, gp95trkB and gpl4Btrke, which bind BDNF (15, 16) and 12,17). gp95,rkB is a truncated receptor lacking the catalytic tyrosine kinase domain (18,19). The trkC locus seems to encode full-length and kinaseless receptors for 21). In addition to these high-affinity receptors, all NTs can also bind with low affinity to a cell surface protein called p75 or the low-affinity NT receptor (LANR) (4,10,15,22,23). The role of this protein is not fully understood but some data indicate that it is required for signal transduction of NGF (24-26). However, NGF mutants thatThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.do not bind to p75 can support neuronal surviv...
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