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Query: UNIPROT:P06889 (Mol)
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We studied the expression of messenger ribonucleic acids (mRNAs) for neurotrophins and neurotrophin receptors in the rat pituitary gland and examined the influence of adrenal hormones on their mRNA levels, using in situ hybridization and Northern blot analysis. The only neurotrophin present at detectable levels in the pituitary was brain-derived neurotrophic factor (BDNF), which was observed in the anterior and intermediate lobes. Several transcripts of the putative receptor for BDNF, trkB, were present in the anterior and posterior lobes of the pituitary. A low amount of trkC mRNA was found in both the anterior and the intermediate lobe. Dexamethasone treatment decreased both BDNF and trkB mRNA levels in the anterior lobe of the pituitary. Adrenalectomy had no effect on trkB expression, but it decreased BDNF mRNA levels in comparison to the control animals. This effect could not be reversed by dexamethasone substitution, suggesting that BDNF, mRNA levels may be regulated not only by glucocorticoids but also by other adrenal hormones. These results demonstrate that BDNF, trkB and trkC are expressed in the pituitary gland and that glucocorticoids and possibly other adrenal hormones may modulate pituitary functions by regulating the expression of neurotrophic factors and their receptors. Whether BDNF acts as a secreted hormone, a trophic factor, or has autocrine/paracrine functions within the pituitary through its receptor, trkB, remains to be studied.
Brain Res Mol Brain Res 1994 Dec
PMID:Neurotrophins and their receptors in the rat pituitary gland: regulation of BDNF and trkB mRNA levels by adrenal hormones. 789 23

Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are two structurally-related neurotrophins synthesized in dentate gyrus granule cells and pyramidal neurons of the hippocampal formation. These neurons receive excitatory glutamatergic afferents from the entorhinal cortex via the angular bundle/perforant path. In the present study, we tested whether electrophysiological stimulation of this glutamatergic pathway modifies NGF or BDNF messenger RNA (mRNA) expression in vivo. Within hours following brief trains of high frequency angular bundle stimulation, the levels of mRNA encoding both neurotrophins were increased exclusively in granule cells of the ipsilateral dentate gyrus. The increase in neurotrophic factor mRNA expression was found to be mediated through the N-methyl-D-aspartate (NMDA) glutamate receptor subtype, and occurred in the absence of seizure. These findings provide evidence that neurotrophic factor mRNA levels in the hippocampal formation are increased by direct activation of excitatory afferents originating in the entorhinal cortex. We suggest that the function of some neurotrophin-responsive neuronal populations may depend upon the integrity and activity of neurons in the entorhinal cortex, a population of neurons reported to be compromised in patients with Alzheimer's disease.
Brain Res Mol Brain Res 1994 Apr
PMID:Neurotrophic factor mRNA expression in dentate gyrus is increased following in vivo stimulation of the angular bundle. 791 2

Reactive gliosis is part of the response of central nervous system to injury and neurodegeneration. Cellular components of the reactive gliosis have the capability to synthesize neurotrophic factors, and thus are capable of affecting the fate of neuronal populations in the injured tissue. In this study, we explored the putative involvement of reactive glia-derived neurotrophins in sustaining the axonal projections of target-deprived neurons. Neuronal targets of the dorsal column nuclei neurons were suppressed through excitotoxic lesion of the ventrobasal complex of the rat thalamus (VB). Despite the development of reactive gliosis, neither up-regulation of NGF, nor BDNF or NT3 mRNA could be detected by solution hybridization in the lesioned site at all times tested. In contrast, expression of the LNGFR gene increased progressively up to 90 days post-lesion. Immunocytochemical studies localized the LNGFR protein in a subset of small cells with ramified processes resembling microglia at 7 and 20 days post-lesion. At longer times, double immunolabelling studies revealed that a substantial part of LNGFR-immunoreactive cells filling the area of neuronal loss were neither microglial cells nor astrocytes although presence of LNGFR in a subset of microglial cells could not be excluded. Previous ultrastructural studies of the kainate-lesioned VB suggest that these LNGFR-immunoreactive cells correspond to oligodendrocytes and/or Schwann cells. At 2 months post-lesion, when LNGFR expression was maximal, increased levels of trkA mRNA were detected in the lesioned site. Immunocytochemical studies revealed the presence of numerous trkA-immunoreactive astrocytes. TrkB mRNA, encoding the full-length high-affinity receptor for BDNF, remained undetectable by non-isotopic in situ hybridization. In contrast to the lack of neurotrophin gene expression by glial components of the lesioned VB, dorsal column nuclei neurons contained NGF mRNA as revealed by in situ hybridization studies at 10 days--prior to enhanced LNGFR expression in the lesion--and 2 months post-lesion. In addition, the number and the staining intensity of NGF mRNA-positive neurons was increased in the target-deprived neurons, as compared with the contra-lateral nucleus projecting to intact targets. These results show that glial cells present in a reactive gliosis which develops in the kainic acid-lesioned thalamus, do not synthesize neurotrophins but instead produce high levels of both low- and high-affinity NGF receptors, LNGFR by Schwann cells/oligodendrocytes and possibly a subset of microglial cells, and trkA by reactive astrocytes.(ABSTRACT TRUNCATED AT 400 WORDS)
Brain Res Mol Brain Res 1994 Jul
PMID:Target-deprived CNS neurons express the NGF gene while reactive glia around their axonal terminals contain low and high affinity NGF receptors. 796 64

A unilateral hypoxia-ischaemia (HI) 21-day-old rat preparation was used to assess the effects of HI on the expression of the immediate-early gene proteins (IEGPs) c-Fos/FRAs, Fos B, c-Jun, Jun B, Jun D, Krox 20, Krox 24, and on the mRNA for the neurotrophic factor, brain-derived neurotrophic factor (BDNF). Moderate HI (15 min hypoxia) produced delayed, selective neuronal death and was associated with a rapid induction of c-Fos, Fos B, Jun B, Jun D, and c-Jun proteins, but not Krox 20 protein or BDNF mRNA, in neurons on the side of HI and also a delayed expression of c-Jun (and to a lesser extent c-Fos/FRA's and Fos B) 24-48 h after HI in neurons that underwent delayed neuronal death. Krox 24 showed an initial induction followed by a long-lasting suppression of its expression in regions undergoing cell loss. Severe HI (60 min hypoxia) resulted in seizures and rapid neuronal loss and infarction (necrotic cell death) on the side of HI, and was associated with early induction of c-Fos, Fos B, c-Jun, Jun B, Jun D, Krox 20 and Krox 24 protein and BDNF mRNA in neurons on the non-ligated side of the brain. Fos, c-Jun, Jun B, Jun D and Krox 24, but not Krox 20, Fos B, or BDNF mRNA, were also induced in non-nerve cells on the damaged side of the brain after both moderate and severe HI, and many of these cells appeared to be dividing. Thus, moderate HI induces IEGP's in neurons and non-nerve cells in damaged regions, whereas severe HI induces IEGP's and BDNF in non-damaged regions. c-Jun (and to a lesser extent c-Fos/FRA's) showed a prolonged expression in neurons undergoing delayed, but not necrotic, cell death suggesting that they may be involved in the biochemical cascade that causes selective delayed neuronal death. BDNF was not induced by HI, and therefore, does not appear to play an endogenous neuroprotective role in the CNS.
Brain Res Mol Brain Res 1994 Aug
PMID:Immediate-early gene protein expression in neurons undergoing delayed death, but not necrosis, following hypoxic-ischaemic injury to the young rat brain. 798 48

In order to get a deeper insight into comprehensive understanding of gene regulation of brain-derived neurotrophic factor (BDNF), we characterized the transcriptional apparatus of this gene on the basis of the genomic structure. The results in this study revealed that there are at least four distinctive promoters in the BDNF gene; two of them are neuron-specific and the rest are active in some non-neuronal tissues as well as neuronal ones. Although the analyses of the promoter usage pattern clarified many characteristic features in controlling these promoter activities, the most notable finding was that administration of kainic acid resulted in great activation of two out of the four promoters in hippocampal neurons in a regionally different manner and thus indicated the presence of two distinct signal transduction pathways for kainate-induced activation of BDNF gene expression in neurons. The analysis of BDNF gene expression in terms of the promoter usage pattern would provide a new and important insight into understanding a molecular control mechanism of this gene expression.
Brain Res Mol Brain Res 1994 Feb
PMID:Distinctive four promoters collectively direct expression of brain-derived neurotrophic factor gene. 817 Mar 45

During embryogenesis, the neurons of vertebrate sympathetic and sensory ganglia become dependent on neurotrophic factors, derived from their targets, for survival and maintenance of differentiated functions. Many of these interactions are mediated by the neurotrophins NGF, BDNF, and NT3 and the receptor tyrosine kinases encoded by genes of the trk family. Both sympathetic and sensory neurons undergo developmental changes in their responsiveness to NGF, the first neurotrophin to be identified and characterized. Subpopulations of sensory neurons do not require NGF for survival, but respond instead to BDNF or NT3 with enhanced survival. In addition to their classic effects on neuron survival, neurotrophins influence the differentiation and proliferation of neural crest-derived neuronal precursors. In both sympathetic and sensory systems, production of neurotrophins by target cells and expression of neurotrophin receptors by neurons are correlated temporally and spatially with innervation patterns. In vitro, embryonic sympathetic neurons require exposure to environmental cues, such as basic FGF and retinoic acid to acquire neurotrophin-responsiveness; in contrast, embryonic sensory neurons acquire neurotrophin-responsiveness on schedule in the absence of these molecules.
Mol Neurobiol
PMID:Development of trophic interactions in the vertebrate peripheral nervous system. 817 44

Levels of mRNA for nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and the tyrosine kinase receptors trkB and trkC have been studied using in situ hybridization in the rat brain after topical application of KCl to the cortical surface (which induces spreading depression). Repeated episodes of spreading depression during 2 h caused a rapid and marked increase of BDNF mRNA levels in deep and, in particular, superficial cortical layers of the ipsilateral hemisphere (to 213 and 417% of control, respectively). Maximal levels were reached within 2 h after the cessation of spreading depression and at 24 h BDNF mRNA expression had returned to control values. Levels of BDNF mRNA were unaffected in the hippocampus, in areas outside the cerebral cortex and in the contralateral hemisphere. Furthermore, no change of the expression of mRNA for NGF, NT-3, trkC or the full length trkB receptor was detected at any time point. However, at 2 h after spreading depression there was an increased level (150% of control) in superficial cortical layers of mRNA hybridizing to an oligonucleotide probe detecting both truncated receptors lacking the tyrosine kinase domain and full length trkB receptors. Also one single episode of spreading depression gave rise to a significant increase of cortical BDNF mRNA levels (to 207% of control), which was attenuated (by 61%) after administration of the competitive NMDA receptor antagonist CGS 19755. The results provide evidence that mild brain insults associated with glutamate release and elevated intracellular calcium, such as spreading depression, also in the absence of seizure activity can lead to activation of the BDNF gene in cortical neurons.
Brain Res Mol Brain Res 1993 Sep
PMID:Rapid increase of BDNF mRNA levels in cortical neurons following spreading depression: regulation by glutamatergic mechanisms independent of seizure activity. 823 31

The spatio-temporal pattern of expression of neurotrophin-3 (NT3), brain-derived neurotrophic factor (BDNF) and low-affinity nerve growth factor receptor (LNGFR) genes was analyzed in the postnatal developing cerebellar system of the rat by in situ hybridization histochemistry. Different ontogenetic patterns of expression were observed for these three genes. In agreement with previously published results (Neuron, 5 (1990) 501-509; Dev. Brain Res., 55 (1990) 288-292) we found that NT3 and LNGFR mRNA peaked early, during the first 2 postnatal weeks, whereas BDNF mRNA peaked later, around postnatal day 20, in the cerebellar cortex. High levels of NT3 mRNA were found in the internal granule cell layer as early as postnatal day 5. NT3 mRNA was also present in the external-premigratory granule cell layer at postnatal day 10. From postnatal day 5 on, LNGFR mRNA was present in the proliferative area of the external granule cell layer and in the Purkinje cells. NT3 mRNA level decreased and BDNF mRNA increased in granule cells concomitantly with their migration and maturation, suggesting a sequential stimulation of these two genes during this developmental process. LNGFR mRNA levels decreased along the same period. Although practically undetectable in the cerebellar granule cell layer in the first two postnatal weeks, BDNF mRNA was transiently expressed in the deep cerebellar nuclei during this time and it was very abundant in the inferior olivary system from postnatal day 5 on. LNGFR mRNA was transiently expressed in the inferior olivary system, in the first postnatal week. These data are discussed in relation to the coordinated postnatal maturation of the different cells of the cerebellar system.(ABSTRACT TRUNCATED AT 250 WORDS)
Brain Res Mol Brain Res 1993 Jan
PMID:Differential expression of brain-derived neurotrophic factor, neurotrophin-3, and low-affinity nerve growth factor receptor during the postnatal development of the rat cerebellar system. 838 92

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

In the adult rat hippocampus mRNA of F1/GAP-43, an axonal growth-associated protein, is highly expressed in pyramidal cells, but is absent in granule cells. To determine whether granule cells can be induced to express mRNA of F1/GAP-43, transcript levels were studied after limbic seizures, which can induce sprouting of granule cell mossy fibers. Seizure-inducing electrolytic lesions were made in the dentate gyrus hilus with stainless-steel electrodes and mRNA levels were measured in contralateral hippocampus by quantitative in situ hybridization. Induction of F1/GAP-43 mRNA expression was observed in granule cells at 24 h, but not at 6 or 12 h, after the hilar lesion. When equivalent sized hilar lesions were made with platinum electrodes, which do not induce seizures, no hybridization was apparent over the granule cells. Hybridization over granule cells had declined by 48 h post-lesion, but even at 10 days it was still slightly higher than in control rats. F1/GAP-43 mRNA expression was also increased 2-fold in CA1 pyramidal cells with peak expression at 48 h post-lesion. These are the first data to our knowledge that demonstrate that F1/GAP-43 gene expression can be altered in neurons located within the adult brain. Induction of F1/GAP-43 mRNA expression in the granule cells may be important for the sprouting of mossy fibers and could be triggered by the elevated levels of brain-derived neurotrophic factor in CA3 cells which precede the increased F1/GAP-43 gene expression in granule cells.
Brain Res Mol Brain Res 1993 Mar
PMID:Induction of F1/GAP-43 gene expression in hippocampal granule cells after seizures [corrected]. 851 May 1


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