Functional interactions of neurotrophins and neurotrophin receptors.
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Animals↗
Biomedical subjects
M Bothwell
Publications and source records attributed to M Bothwell.
Noradrenergic neurons in the locus coeruleus of birds express TrkA, transport NGF, and respond to NGF.
The chicken locus coeruleus contains a population of noradrenergic neurons which express the neurotrophin receptor p75 (von Bartheld and Bothwell, 1992). To determine which neurotrophin may regulate the development of noradrenergic neurons in the chicken locus coeruleus, expression of trk receptors, retrograde transport of neurotrophins, and responses to NGF were examined. P75-expressing noradrenergic neurons were found to project to the basal forebrain. They transport radio-iodinated NGF after injections into this target. The retrograde transport of NGF is specific to the noradrenergic neuronal population as evidenced by double labeling with antibodies against dopamine-beta-hydroxylase. The same neuronal population expresses trkA receptor mRNA. The size of noradrenergic neurons in the locus coeruleus proper, but not in the nucleus subcoeruleus, is significantly increased after injections of NGF into the telencephalon, consistent with the hypothesis that target-derived NGF provides trophic support. Noradrenergic coeruleus neurons are rescued from toxic effects of 6-hydroxydopamine injected into the telencephalon when NGF is injected into the midbrain. NGF has no rescue effect when it is coinjected with 6-hydroxy-dopamine into the telencephalon. In explant or dissociated cultures, noradrenergic coeruleus neurons do not respond to elevated levels of NGF with increased neurite outgrowth. Taken together, these results suggest that NGF plays a role in the development and maintenance of noradrenergic coeruleus neurons in the chick brain. The data also support our previous conclusion that major species differences exist between birds (chicken) and mammals with regard to trophic regulation of presumptive homologous neuronal populations.
Animals↗
Electron microscopic localization of nerve growth factor receptor (p75)-immunoreactivity in pars caudalis/medullary dorsal horn of the cat.
Previous studies have demonstrated the presence of nerve growth factor receptor [NGFr(p75)]-immunoreactivity (IR) in the spinal trigeminal nucleus of both 8-10 week-old kittens and mature cats. Most of the NGFr(p75)-IR is lost following retrogasserian rhizotomy, indicating that the majority of the NGFr(p75)-IR within the spinal trigeminal nucleus is of trigeminal primary afferent origin. Here, we examined the ultrastructural localization of NGFr(p75)-IR within lamina II outer of pars caudalis/medullary dorsal horn in the mature cat. Lamina II outer represents a location where dense NGFr(p75)-IR is seen with the light microscope. The NGFr(p75)-IR identified with the electron microscope was located within small thinly myelinated and unmyelinated axons and within axon terminals. The terminals with NGFr(p75)-IR typically formed asymmetric synaptic specializations onto dendritic profiles and at times were postsynaptic to other axon terminals at symmetric synaptic specializations. The terminals with NGFr(p75)-IR were either simple (associated with a single profile) or more complex, such as those that typically formed the central element in synaptic glomeruli. The NGFr(p75)-IR in terminals was especially prominent on microtubules and the plasmalemma and these findings are consistent with proposed roles for NGFr(p75) in axoplasmic/neuronal transport and as a membrane protein, respectively. The profiles with NGFr(p75)-IR seen with the electron microscope indicate a primary afferent origin and show some similarities when compared to other markers of primary afferent fibers such as calcitonin gene-related peptide. In addition, a possible role for NGFr(p75) in the transmission of nociceptive stimuli is also discussed.
Animals↗
Activity assays of nine heterogeneous promoters in neural and other cultured cells.
To express high levels of proteins encoded by transfected DNA constructs in a variety of cultured cells, including neuronal cells, the activities of nine different promoters were evaluated using Escherichia coli beta-galactosidase (beta-gal) (LacZ) as a reporter gene. These nine promoters were categorized into three distinct groups (high, intermediate, and low expresser), in terms of the levels of beta-gal expression. An expression vector containing the cytomegalovirus enhancer and the chick beta-actin promoter (high expresser) showed the highest levels of expression, followed by vectors containing the cytomegalovirus promoter/enhancer and the SV40 promoter/enhancer (intermediate expresser). The rest of the promoters (thymidine kinase, adenovirus, murine proliferative sarcoma virus, nerve growth factor receptor, Rous sarcoma and mouse mammary tumor virus, and beta-amyloid precursor protein) expressed low levels of beta-gal. These results were consistent for eight different cell types. A particularly attractive model is the stem cell, P19; cultures differentiating into progeny consisting predominantly of cholinergic neurons could be readily transfected with expression vectors using liposomes and expressed beta-gal without significant morphologic changes of the differentiated neurons. The systems should be useful for the study of promoters and various expressed proteins, including those involved in axonal transport.
Animals↗
Expression of BDNF and NT-3 mRNA in hair cells of the organ of Corti: quantitative analysis in developing rats.
Brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) are synthesized by inner and outer hair cells of the developing organ of Corti. This raises the possibility that the reorganization of cochlear innervation patterns that occurs postnatally may be influenced by changing levels of neurotrophin expression. To determine if differential expression of BDNF or NT-3 in the inner and outer hair cells correlates with the reorganization of afferent and efferent innervation, we used in situ hybridization techniques to quantify relative levels of transcript biosynthesis in hair cells of developing rats. BDNF transcripts decreased in inner and outer hair cells from E17 to insignificant levels at P4. NT-3 expression was high at E17 in inner and outer hair cells, decreased in outer hair cells by E21, in inner hair cells by P1, remained low during the first postnatal week and was increased in the adult. The decreases in expression of both neurotrophins at birth precede the retraction of afferent nerve terminals from outer hair cells. BDNF and NT-3 transcription decreases substantially in outer hair cells between E21 and P4 when efferent innervation begins, indicating target biosynthesis of these neurotrophins is not likely to be instrumental in efferent target selection.
Animals↗
Neurotrophin and neurotrophin receptor mRNA expression in developing inner ear.
Receptors which bind the neurotrophins NGF, BDNF, NT-3 and NT-4/5 were shown to be present in cochlear and vestibular ganglion cells during development, implying a neurotrophic role for these molecules in the inner ear. We have found by in situ hybridization that cochlear and vestibular sensory epithelial cells express BDNF and NT-3 mRNAs, but neither NGF or NT-4 mRNAs, in mouse embryos from embryonic day (E)11.5 through postnatal day (P)1. NT-3 mRNA was expressed throughout the sensory epithelium whereas BDNF mRNA appeared to be localized in hair cells (vestibular) and epithelial precursors of hair cells (cochlea). BDNF mRNA was also expressed in a subpopulation of cells in the cochleovestibular ganglion at E11.5 and E12.5. Additionally, cochlear and vestibular neurons contained mRNAs encoding the neurotrophin receptors p75 and trkB. TrkA mRNA was transiently expressed in cochleovestibular ganglion cells at E12.5. These data suggest that BDNF and NT-3 play a role in cochleovestibular neuron survival and neurite outgrowth during development in the inner ear.
Animals↗
Positive and negative effects of neurotrophins on the isthmo-optic nucleus in chick embryos.
The survival of neurons in the developing isthmo-optic nucleus (ION) is believed to depend on the retrograde transport of trophic molecules from the target, the contralateral retina. We now show that ION neurons transport nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) retrogradely and that BDNF and NT-3 support the survival of ION neurons in vivo and promote neurite outgrowth in vitro. Surprisingly, NGF enhanced normal developmental cell death in vivo in a dose-dependent way. These findings show that increased levels of NGF can have adverse effects on differentiated neurons. The negative effect of NGF could be mimicked by intraocular injection of antibodies that block binding of neurotrophins to the 75 kd neurotrophin receptor (p75). These data implicate a role for the p75 receptor in NGF's neurotoxicity and indicate that this receptor is involved in the mechanism by which ION neurons respond to BDNF and NT-3 in the target.
Animals↗
Neurotrophins in the developing and adult primate adenohypophysis: a new pituitary hormone system?
Expression of neurotrophins and of the low-affinity neurotrophin receptor p75 was examined immunocytochemically in pituitary glands of twelve developing and adult macaques, ranging in age from fetal day 100 through age 5 years. Neurotrophins were identified by labeling with a rabbit polyclonal antiserum raised against purified mouse nerve growth factor, which recognizes brain-derived neurotropic factor and neurotrophin-3 as well. During pituitary morphogenesis, neurotrophins were present in epithelial cells distributed throughout all divisions of the anterior pituitary (pars distalis, pars intermedia, and pars tuberalis). Near term and in the adult, neurotrophin-immunoreactive cells were fewer in number and their distribution was limited to the pars distalis and pars tuberalis. A monoclonal antibody against the human neurotrophin receptor p75 heavily labeled mesenchymal boundary structures and blood vessels in the developing gland, and several populations of glial-like cells with a presumed paracrine function (folliculostellate cells in the pars distalis, and pituicytes and tanycytes in the neural lobe and infundibulum, respectively) as well as axons innervating the portal vasculature in postnatal specimens. These complementary patterns of neurotrophin and receptor expression suggest a possible inductive role for neurotrophins in pituitary morphogenesis and in the establishment of hypothalamic neural and hormonal control of pituitary function. In the adult anterior pituitary, examined using double-label immunocytochemistry for neurotrophins and conventional anterior-pituitary hormones, neurotrophins did not colocalize with human prolactin, human adrenocorticotropic hormone, recombinant human growth hormone, or the beta subunits of human luteinizing hormone, human follicle-stimulating hormone, or human thyrotropin. Neurotrophin-containing cells therefore appear to be a distinct population, suggesting novel paracrine or endocrine functions for this family of neuropeptides.
Aging↗
A biphasic change in ribosomal conformation during transneuronal degeneration is altered by inhibition of mitochondrial, but not cytoplasmic protein synthesis.
Following loss of eighth nerve input, 20-40% of neurons in the neonatal chick cochlear nucleus, nucleus magnocellularis (NM), undergo cell death. Intracellular changes that precede the death of NM neurons include increased oxidative metabolism and mitochondrial volume, decreased cytoplasmic protein synthesis, and destruction of ribosomes. Six hours following afferent deprivation, dying NM neurons demonstrate complete loss of ribosomes and cessation of protein synthesis, suggesting that the rapid destruction of ribosomes leads to neuronal death. Increased NM neuron death occurs when mitochondrial upregulation is prevented by chloramphenicol, a mitochondrial protein synthesis inhibitor. This finding suggests that increased oxidative capacity is required for neuronal survival following loss of afferent input. To study changes in the ribosomes of afferent-deprived NM neurons, we obtained a monoclonal antibody to ribosomal RNA. This monoclonal antibody, Y10B, labels ribosomes of all NM neurons receiving normal synaptic activity. Following removal of afferent input, NM neurons demonstrate a biphasic change in their pattern of Y10B label. During the initial phase, there is a uniform decrease in the density of Y10B label. In the second phase, some NM neurons recover the capacity to bind the Y10B antibody while others remain unlabeled. During this second phase, NM neurons putatively destined to die, based on their failure to synthesize protein, are unlabeled by the Y10B antibody. New gene expression is not necessary to initiate the change in ribosomal immunoreactivity that leads deafferented NM neurons toward cell death. Blocking cytoplasmic protein synthesis with cycloheximide had no effect on the biphasic change in Y10B labeling of afferent-deprived NM neurons. Treating chicks with chloramphenicol, however, prevented the recovery of Y10B immunoreactivity in NM neurons during the second phase of the response to afferent deprivation.
Afferent Pathways↗
Nerve growth factor receptor (p75)-immunoreactivity in the normal adult feline trigeminal system and following retrogasserian rhizotomy.
The 75 kDa protein nerve growth factor receptor [NGFr(p75)] is a neurotrophin receptor that is able to bind different members of the neurotrophin family of molecules implicated in affecting neuronal survival. Here we describe the light microscopic distribution of NGFr(p75)-immunoreactivity (IR) within the feline trigeminal brainstem sensory nuclear complex and trigeminal ganglion of normal adult subjects and in subjects 10 and 30 days following retrogasserian rhizotomy. Within the trigeminal ganglion of normal subjects, numerous fibers and most of the neuronal cell bodies showed NGFr(p75)-IR that varied in intensity, while cells and fibers with NGFr(p75)-IR were less numerous within the mesencephalic trigeminal nucleus. Within the main sensory and spinal trigeminal nuclei, NGFr(p75)-IR formed a reproducible pattern that varied between the different subnuclei. The NGFr(p75)-IR consisted both of dense pockets and a low level NGFr(p75)-IR that was selective to the trigeminal neuropil. Following rhizotomy, most of the NGFr(p75)-IR was lost from the main sensory and spinal trigeminal nuclei, except in regions where the upper cervical roots and cranial nerves VII, IX, and X project. In contrast, examination of the central root that was still attached to the trigeminal ganglion showed increased NGFr(p75)-IR in fibers and supporting cells, as did the motor root within the peripheral mandibular division. These results indicate that the majority of the NGFr(p75)-IR within the main sensory and spinal trigeminal nuclei originates from primary trigeminal afferents and that retrogasserian rhizotomy leads to an up-regulation of NGFr(p75)-IR in the part of the central root that is contiguous with the ganglion.
Animals↗
Basic fibroblast growth factor promotes adhesive interactions of neuroepithelial cells from chick neural tube with extracellular matrix proteins in culture.
Fibroblast growth factors have been increasingly assigned mitogenic and trophic roles in embryonic and postnatal development of the nervous system. Little is known, however, of their functional roles in early embryonic neural development at the neural tube stage. We have examined the effect of basic fibroblast growth factor (bFGF) on the adhesive behavior in culture of dissociated brachio-thoracic neural tube cells from 26- to 30-somite stage chick embryos. Cells plated on collagen-coated substratum at a low density attach to the substratum but show poor cell spreading. Addition of bFGF markedly promotes cell spreading, yielding an epithelial morphology. This effect becomes discernible 6-8 hours after cell plating with bFGF and is completed by 24 hours, with half-maximal and maximal effects attained at around 0.4 and 10 ng/ml, respectively. The number of cells remain largely constant up to 24 hours, and then cell survival and/or mitogenic effects of bFGF become apparent. The cell spreading effect is abolished by cycloheximide treatment, inhibited by the anti-beta 1-integrin antibody CSAT, and accompanied by about twofold increases in the expression of beta 1-integrin and vinculin, components of focal adhesion complexes. Cells cultured with bFGF for 24 hours exhibit enhanced cell attachment and cell spreading with little time lag following cell plating. In earlier embryonic stages, developmentally less mature cells depend much more on bFGF for their cell spreading and survival, while in later stages the cell spreading response to bFGF becomes undetectable as neural tube develops to spinal cord. The cell spreading effect of bFGF is realized on specific extracellular matrix proteins including laminin, fibronectin and collagen, but not on vitronectin, arg-gly-asp peptide (PepTite-2000), poly-L-ornithine or others. These results suggest that, in an early stage of neural tube development, bFGF is involved in the developmental regulation of adhesive interactions between neuroepithelial cells and the extracellular matrix, thereby controlling their proliferation, migration and differentiation.
Animals↗
Nerve growth factor receptor expression in fetal, mature, and diseased human kidneys.
BACKGROUND: Nerve growth factor (NGF) has been proposed to be critical to normal renal development in rodents. However, little is known about expression of NGF or its receptors in human kidneys, or their potential function in development or disease. EXPERIMENTAL DESIGN: A previously characterized monoclonal antibody (NGFR 5) was utilized for immunohistochemical localization of the p75 NGF receptor (NGFR) in alcohol-fixed tissue sections of human fetal kidney (N = 27, 54 to 105 days gestation), normal mature kidney obtained from nephrectomies for neoplasia (N = 7), and renal biopsies (N = 54) with various glomerulopathies previously characterized for degree of mesangial alpha smooth muscle actin (alpha SM) expression. A second monoclonal antibody (NGFR2) was also utilized on fetal and normal kidney. Immunohistochemical localization of alpha SM and proliferating cell nuclear antigen expression was also performed. RESULTS: Glomerular expression of NGFR in the fetus is limited to the mesangium in later stages of glomerulogenesis; at these stages this expression is similar to that which has been previously reported for platelet-derived growth factor receptor-beta and alpha SM. There is focal, weak persistence of NGFR in normal adult glomeruli, similar to alpha SM. In renal biopsies, glomerular NGFR expression was upregulated in a variety of disease states, which frequently but not invariably correlated with alpha SM expression. Fetal and adult expression of NGFR is also prominent in periarterial connective tissue cells and nerve. Apparent de novo expression by many interstitial cells in normal and diseased adult kidneys is also present. CONCLUSIONS: These studies indicate: (a) NGF or other neurotrophins that bind NGFR may be important in human kidney development and glomerular response to injury; (b) NGFR is a marker of developing mesangial cells similar to alpha SM and platelet-derived growth factor receptor-beta; (c) enhanced expression of NGFR, like alpha SM, is a marker of mesangial cell injury or activation, and that their coordinate upregulation in some glomerular disease states appears to recapitulate a normal developmental state; (d) a population of NGFR and platelet-derived growth factor-beta expressing interstitial cells can be identified in normal kidneys, which suggests potential signaling mechanisms to recruit or activate these cells at sites of tubulointerstitial injury.
Antibodies, Monoclonal↗
Analysis of low affinity nerve growth factor receptor during pulpal healing and regeneration of myelinated and unmyelinated axons in replanted teeth.
Nerve regeneration was examined in rat molars that were briefly extracted and then replanted in the socket for 1-90 days. Immunocytochemistry was used to evaluate neural and nonneural immunoreactivity (IR) for low affinity nerve growth factor receptor (p75-NGFR) and for laminin and calcitonin gene-related peptide (CGRP). Three different types of pulpal response to replantation were found. Type I: Some replanted teeth had mild injury and still contained coronal odontoblasts and associated fibroblasts that retained p75-NGFR-IR; they continued regular dentin formation and had excellent reinnervation. Type II: Teeth with intermediate injury lost most or all of the coronal pulp tissue, but they regenerated odontoblast-like cells that formed irregular dentin, they had numerous dispersed p75-NGFR-IR fibroblasts in crown pulp during early regeneration, and they had excellent reinnervation. Type III: Severely injured teeth lost their original pulp; they filled with dense connective tissue and bone and had poor reinnervation. After Type I or II injury the Schwann cells around degenerating myelinated and unmyelinated axons had increased expression of p75-NGFR by 1-3 days. By 7-10 days those Schwann cells had formed hollow tubes (bands of Bungner) along the degenerating axon tracks. They maintained their increased p75-NGFR-IR during and after regeneration of unmyelinated axons, whereas Schwann cells involved in remyelination lost p75-NGFR-IR at that stage. The number of CGRP-IR axons in the regenerating pulp increased from 7 to 90 days. Laminin-IR increased in all replanted teeth at 3-10 days and only returned to normal patterns in teeth with Type I or Type II response at 20-90 days. The special p75-NGFR-IR of pulpal fibroblasts of adult rat molars did not usually persist in regenerated, reinnervated pulp. The extensive depletion of fibroblast p75-NGFR-IR and the continuing enhanced p75-NGFR-IR in unmyelinated nerve fibers at 90 days show that altered growth factor conditions characterize regenerated pulp of replanted teeth.
Animals↗
Cholinergic innervation of the human striatum, globus pallidus, subthalamic nucleus, substantia nigra, and red nucleus.
The anatomical organization of cholinergic markers such as acetylcholinesterase, choline acetyltransferase, and nerve growth factor receptors was investigated in the basal ganglia of the human brain. The distribution of choline acetyltransferase-immunoreactive axons and varicosities and their relationship to regional perikarya showed that the caudate, putamen, nucleus accumbens, olfactory tubercle, globus pallidus, substantia nigra, red nucleus, and subthalamic nucleus of the human brain receive widespread cholinergic innervation. Components of the striatum (i.e., the putamen, caudate, olfactory tubercle, and nucleus accumbens) displayed the highest density of cholinergic varicosities. The next highest density of cholinergic innervation was detected in the red nucleus and subthalamic nucleus. The level of cholinergic innervation was of intermediate density in the globus pallidus and the ventral tegmental area and low in the pars compacta of the substantia nigra. Immunoreactivity for nerve growth factor receptors (NGFr) was confined to the cholinergic neurons of the basal forebrain and their processes. Axonal immunoreactivity for NGFr was therefore used as a marker for cholinergic projections originating from the basal forebrain (Woolf et al., '89: Neuroscience 30:143-152). Although the vast majority of striatal cholinergic innervation was NGFr-negative and, therefore, intrinsic, the striatum also contained NGFr-positive axons, indicating the existence of an additional cholinergic input from the basal forebrain. This basal forebrain cholinergic innervation was more pronounced in the putamen than in the caudate. The distribution of NGFr-positive axons suggested that the basal forebrain may also project to the globus pallidus but probably not to the subthalamic nucleus, substantia nigra, or red nucleus. The great majority of cholinergic innervation to these latter three structures and to parts of the globus pallidus appeared to come from cholinergic neurons outside the basal forebrain, most of which are probably located in the upper brainstem. These observations indicate that cholinergic neurotransmission originating from multiple sources is likely to play an important role in the diverse motor and behavioral affiliations that have been attributed to the human basal ganglia.
Acetylcholinesterase↗
Development and distribution of noradrenergic and cholinergic neurons and their trophic phenotypes in the avian ceruleus complex and midbrain tegmentum.
We investigated the development of noradrenergic and cholinergic neurons in the ceruleus complex and mesencephalic tegmentum in embryonic and posthatch chickens and compared the distribution of transmitter phenotypes with the expression of nerve growth factor receptor (NGFR) mRNA and fibroblast growth factor receptor (FGFR) mRNA. Noradrenergic and cholinergic neurons were visualized by using antibodies against dopamine-beta-hydroxylase (DBH) and choline acetyltransferase (ChAT), respectively. Expression of receptors for trophic factors was determined by using in situ hybridization techniques. Noradrenergic neurons concentrate in caudal parts of the locus ceruleus and nucleus subceruleus. Cholinergic ceruleus neurons are abundant in the nucleus mesencephalicus profundus, pars ventralis (MPv) as well as in the nucleus subceruleus and locus ceruleus. This cholinergic population resembles the cholinergic pontomesencephalotegmental complex of mammals. Both DBH and ChAT label is evident at and after six days of incubation (E6). The distribution and numbers of immunolabeled neurons are similar in the embryonic and posthatch chick. Initially, many tegmental and ceruleus neurons express substantial levels of NGFR mRNA (E7-E9). After E9, expression of NGFR mRNA decreases in most of these neurons, except for a distinct subpopulation of neurons in caudal parts of the ceruleus complex with increased levels of NGFR transcripts. These NGFR-positive neurons coincide in number and distribution with the noradrenergic subpopulation of the ceruleus complex (800-900 neurons). Expression of FGFR mRNA was first detected in ceruleus neurons at E13. Neurons with FGFR transcripts have the same number and distribution as the neurons with the cholinergic phenotype (2,000-2,300 neurons). Transmitter heterogeneity in the ceruleus complex is reflected by a heterogeneity of receptors for trophic factors, with NGFR expressed in the noradrenergic subpopulation, and FGFR expressed in the cholinergic subpopulation. These findings provide evidence for new chemoarchitectonic subdivisions of the avian ceruleus complex. The data showing onset of ChAT expression prior to the onset of FGFR expression argue against a role of FGFR in the determination of the cholinergic transmitter phenotype. Expression of NGFR in the noradrenergic ceruleus subpopulation reveals remarkable species differences as compared to mammals.
Animals↗
Neurotrophin expression in rat hippocampal slices: a stimulus paradigm inducing LTP in CA1 evokes increases in BDNF and NT-3 mRNAs.
We report that stimulation inducing long-term potentiation (LTP) in the CA1 pyramidal cell layer of the hippocampus evokes significant increases in both BDNF and NT-3 mRNAs in CA1 neurons. No changes in BDNF or NT-3 mRNA levels were seen in the nonstimulated regions of the pyramidal cell layer or the dentate. No change was seen in the levels of NGF mRNA at the time point examined. These results suggest that relatively normal levels of activity may regulate region-specific neurotrophin levels in the hippocampus. Given that known effects of NGF (and presumably of BDNF and NT-3) include elevation of neurotransmitter levels, elevation of sodium channels, and promotion of axonal terminal sprouting, activity-associated changes in neurotrophin levels may play a role in regulating neural connections in the adult as well as the developing nervous system.
Animals↗
Novel roles for neurotrophins are suggested by BDNF and NT-3 mRNA expression in developing neurons.
The results of our in situ hybridization experiments demonstrate that sensory neurons, sympathetic neurons, and motoneurons express brain-derived neurotrophic factor and/or neurotrophin-3 mRNAs during development in mouse. In accordance with previous data, we also find neurotrophins in the targets of sensory neurons (skin) and motoneurons (muscle) and the neurotrophin receptors p75, trkA, and trkB in sensory and sympathetic ganglia. These results suggest that neurotrophins have roles other than being target-derived factors that support neuron survival during developmental cell death (neurotrophic hypothesis), but may be transported in an orthograde fashion in neurons and released from axon terminals. We discuss several novel roles for neurotrophins, including autocrine/paracrine regulation of neuron survival, regulation of Schwann cell activity, and neuron to target signaling.
Animals↗
Basic fibroblast growth factor enhances nerve growth factor receptor gene promoter activity in human neuroblastoma cell line CHP100.
The human neuroblastoma cell line CHP100 provides a useful model system in which to study the molecular mechanisms of transcriptional regulation of the low-affinity nerve growth factor receptor (NGFR) gene during neuronal development. Basic fibroblast growth factor (bFGF) induced morphological changes in CHP100 cells, including flattening of cell bodies and neurite outgrowth. bFGF also increased p75NGFR immunoreactivity, as assessed by immunocytochemistry, and increased p75NGFR mRNA levels, as assessed by Northern (RNA) blot analysis. A chimeric gene consisting of 6.7 kb of the 5'-flanking region of the human NGFR gene linked to the chloramphenicol acetyltransferase gene was constructed. In stable transformants of CHP100 cells, 10 ng of bFGF per ml induced an eightfold increase in chloramphenicol acetyltransferase activity. These results indicate that upstream elements of the NGFR gene mediate transcriptional regulation by bFGF.
Base Sequence↗