Showing papers by "Nancy Y. Ip published in 1993"
TL;DR: Reports that acute exposure to neurotrophin-3 (NT-3) or brain-derived neurotrophic factor (BDNF)5, but not nerve growth factor (NGF)6, rapidly potentiates the spontaneous and impulse-evoked synaptic activity of developing neuromuscular synapses in culture provide evidence for the regulation of the function of developing synapses by neurotrophins.
Abstract: THE neurotrophins are a family of neurotrophic factors that promote survival and differentiation of various neuronal populations1,2. Although the long-term effects of neurotrophins on neuronal survival and differentiation have been intensively studied, nothing is known about their effects on synaptic function. Here we report that acute exposure to neurotrophin-3 (NT-3)3,4 or brain-derived neurotrophic factor (BDNF)5, but not nerve growth factor (NGF)6, rapidly potentiates the spontaneous and impulse-evoked synaptic activity of developing neuromuscular synapses in culture. The effect appears to be presynaptic in origin and to be mediated by the Trk family of receptor tyrosine kinases7. These results provide evidence for the regulation of the function of developing synapses by neurotrophins.
758 citations
TL;DR: The ciliary neurotrophic factor receptor complex is shown here to include the CNTF binding protein (CNTFR alpha) as well as the components of the leukemia inhibitory factor (LIF) receptor, LIFR beta (the LIF binding protein) and gp130 [the signal transducer of interleukin-6 (IL-6)].
Abstract: The ciliary neurotrophic factor (CNTF) receptor complex is shown here to include the CNTF binding protein (CNTFR alpha) as well as the components of the leukemia inhibitory factor (LIF) receptor, LIFR beta (the LIF binding protein) and gp130 [the signal transducer of interleukin-6 (IL-6)]. Thus, the conversion of a bipartite LIF receptor into a tripartite CNTF receptor apparently occurs by the addition of the specificity-conferring element CNTFR alpha. Both CNTF and LIF trigger the association of initially separate receptor components, which in turn results in tyrosine phosphorylation of receptor subunits. Unlike the IL-6 receptor complex in which homodimerization of gp130 appears to be critical for signal initiation, signaling by the CNTF and LIF receptor complexes depends on the heterodimerization of gp130 with LIFR beta. Ligand-induced dimerization of signal-transducing receptor components, also seen with receptor tyrosine kinases, may provide a general mechanism for the transmission of a signal across the cell membrane.
657 citations
TL;DR: It is found that a neuronal environment does restrict the Trks in their ability to respond to their "nonpreferred" neurotrophin ligands, providing evidence against a role for accessory molecules expressed in neurons in generating receptors that would allow for responses to lower concentrations of the neurotrophins.
524 citations
TL;DR: It is demonstrated that a transfected CNTFR alpha gene is sufficient to confer CNTF responsiveness upon hemopoietic cells normally responsive only to LIF, providing evidence that CNTFr alpha is a required receptor component that uniquely characterizes CNTF-responding cells.
406 citations
TL;DR: This paper identified transcripts encoding several different forms of rat TrkC, a member of the Trk family of receptor tyrosine kinases that serves as a receptor for neurotrophin-3.
389 citations
TL;DR: These findings not only demonstrate that the CNTF receptor alpha chain is a required component of the functionalCNTF receptor complex but also reveal that it can function in soluble form as part of a heterodimeric ligand.
Abstract: The alpha component of the receptor for ciliary neurotrophic factor (CNTF) differs from other known growth factor receptors in that it is anchored to cell membranes by a glycosylphosphatidylinositol linkage. One possible function of this type of linkage is to allow for the regulated release of this receptor component. Cell lines not normally responsive to CNTF responded to treatment with a combination of CNTF and a soluble form of the CNTF alpha receptor component. These findings not only demonstrate that the CNTF receptor alpha chain is a required component of the functional CNTF receptor complex but also reveal that it can function in soluble form as part of a heterodimeric ligand. Potential physiological roles for the soluble CNTF receptor are suggested by its presence in cerebrospinal fluid and by its release from skeletal muscle in response to peripheral nerve injury.
370 citations
TL;DR: The results suggest that several of the neurotrophins have important effects in the differentiation and maintenance of function of subpopulations of hippocampal neurons.
Abstract: To investigate the possibility of neurotrophins acting directly on hippocampal neurons, we first examined expression of the trk receptors in sections of adult rat brain and in cultures of embryonic rat hippocampus, and then investigated general and specific responses of cultured hippocampal neurons to each of the neurotrophins. In situ hybridization studies indicated high levels of expression of trkB and trkC but not trkA in pyramidal cells, dentate granule neurons, and scattered interneurons. Cultures of embryonic day 18 (E18) hippocampal neurons were also found by Northern analysis to express trkB and trkC but not trkA, indicating potential responsiveness to brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and NT-4, but not NGF. Phosphorylation experiments indeed showed that BDNF, NT-3, and NT- 4 produced rapid tyrosine phosphorylation of Trk proteins, as detected by immunoprecipitation using a pan-Trk-specific antibody, whereas NGF produced no detectable tyrosine phosphorylation in hippocampal cultures. Similarly, all of the neurotrophins, except NGF, induced expression of c-fos mRNA and c-fos protein in these cultures. c-Fos protein induction was detectable in approximately 40–50% of the cells. While we observed no major effect of any of the neurotrophins upon the survival of E18 hippocampal neurons, BDNF, NT-3, and NT-4, but not NGF, produced marked increases in the number of neurons expressing detectable levels of either calbindin or AChE. NT-3 produced the greatest increase in the number of calbindin-positive neurons, whereas BDNF and NT-4 produced the greater increase in the number of AChE- positive neurons. Our results suggest that several of the neurotrophins have important effects in the differentiation and maintenance of function of subpopulations of hippocampal neurons.
352 citations
TL;DR: It is concluded that CNTF is markedly increased as a function of injury to the CNS and that its expression is most likely restricted to reactive astrocytes in the glial scar.
Abstract: Ciliary neurotrophic factor (CNTF) is a pleiotropic molecule that acts as a neurotrophic factor for a wide range of embryonic neurons as well as a differentiation factor for sympathetic neuroblasts and O2A progenitor cells in culture. CNTF messenger RNA (mRNA) is present at very low levels in the normal adult rat central nervous system (CNS), but is dramatically up-regulated after an aspiration lesion of dorsal hippocampus and overlying cortex, in the area coincident with glial scar. The increased level of CNTF mRNA in lesioned hippocampus is maximal by 3 days and is sustained for up to 20 days, the longest time point examined. In contrast, mRNA levels for brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) were slightly decreased during the same period. In situ hybridization experiments revealed that cells expressing CNTF mRNA were concentrated at the margin of the wound, and also present within the gelfoam which filled the lesion cavity. This distribution of CNTF-expressing cells corresponded very closely to that of cells expressing high levels of glial fibrillary acidic protein mRNA at the wound site. Paralleling the observed increase in CNTF mRNA, increased levels of CNTF-like neurotrophic activity were apparent in soluble extracts of the lesioned tissues. This neurotrophic activity for ciliary ganglion neurons was completely blocked by the addition of neutralizing antiserum against CNTF. Basic fibroblast growth factor, which has been shown by others to increase after a similar lesion paradigm (Frautschy et al., Brain Res., 553, 291–299, 1991), does not contribute appreciably to this trophic activity. We conclude that CNTF is markedly increased as a function of injury to the CNS and that its expression is most likely restricted to reactive astrocytes in the glial scar.
250 citations
TL;DR: Supporting the findings that spinal cholinergic neurons are responsive to trophic actions of members of the neurotrophin family, motor neuron‐enriched cultures were found to express mRNA for Trk B and Trk C, which have been identified as high‐affinity receptors for BDNF andNT‐4/5, and NT‐3, respectively.
Abstract: Although developing motor neurons express low-affinity nerve growth factor (NGF) receptors, there is no known biological effect of NGF on developing or adult motor neurons. In this study, we found that, unlike NGF, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5) stimulated cholinergic phenotype by increasing choline acetyltransferase (CAT) activity in cultures enriched with embryonic rat motor neurons. Ciliary neurotrophic factor (CNTF) also stimulated CAT activity. The effects of BDNF and NT-4/5 on CAT activity appeared to be synergistic with that of CNTF. Cotreatment with BDNF and NT-3 resulted in an additive effect, suggesting that signal transduction was mediated through different high-affinity receptors tyrosine kinases B and C (Trk B and Trk C). However, cotreatment with BDNF and NT-4/5 did not result in an increase in CAT activity greater than that of either BDNF or NT-4/5 alone, suggesting that their effects were mediated via the same receptor Trk B. Supporting our findings that spinal cholinergic neurons are responsive to trophic actions of members of the neurotrophin family, motor neuron-enriched cultures were found to express mRNA for Trk B and Trk C, which have been identified as high-affinity receptors for BDNF and NT-4/5, and NT-3, respectively.
191 citations
TL;DR: In adult rats, target-derived NGF, BDNF, and NT3 do not regulate the survival of septal cholinergic neurons in proportion to the number of target neurons present, and the findings suggest that one or more of these target- derived neurotrophins regulate the structural and chemical phenotype of these neurons in the adult.
Abstract: The effect of unilateral excitotoxic ablation of hippocampal neurons was investigated on (1) the local production of mRNA for NGF and related neurotrophins, (2) the amount of NGF protein in the septal region, and (3) the viability and appearance of afferent septal cholinergic neurons in adult rats. After near complete ablation of hippocampal neurons, total levels of NGF, brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT3) mRNA measured by quantitative Northern blot analysis in the hippocampal remnant fell significantly, to less than 25% of control values by 28 d and to less than 9% by 300 d. In the septal region ipsilateral to such lesions, NGF protein levels measured by ELISA fell significantly, to about 35% of control values, but the number of immunohistochemically detected cholinergic neurons did not decline significantly for up to 500 d. Instead, the cholinergic neurons persisted in an atrophied state, exhibiting severe shrinkage and reduced staining for the transmitter-synthesizing enzyme ChAT. The parameters of cell size and ChAT staining intensity correlated significantly with the amount of hippocampal tissue present. These findings indicate that in adult rats, target-derived NGF, BDNF, and NT3 do not regulate the survival of septal cholinergic neurons in proportion to the number of target neurons present. Moreover, the findings suggest that one or more of these target-derived neurotrophins regulate the structural and chemical phenotype of these neurons in the adult.
168 citations
TL;DR: The first example of ciliary neurotrophic factor responsiveness in cells residing outside of the nervous system is shown by demonstrating that embryonic stem cells express a functional ciliary Neurotrophic factor receptor complex, and that ciliary neurology factor is similar to leukemia inhibitory factor in its ability to maintain the pluripotentiality of these cells.
Abstract: Ciliary neurotrophic factor was discovered based on its ability to support the survival of ciliary neurons, and is now known to act on a variety of neuronal and glial populations. Two distant relatives of ciliary neurotrophic factor, leukemia inhibitory factor and oncostatin M, mimic ciliary neurotrophic factor with respect to its actions on cells of the nervous system. In contrast to ciliary neurotrophic factor, leukemia inhibitory factor and oncostatin M also display a broad array of actions on cells outside of the nervous system. The overlapping activities of leukemia inhibitory factor, oncostatin M and ciliary neurotrophic factor can be attributed to shared receptor components. The specificity of ciliary neurotrophic factor for cells of the nervous system results from the restricted expression of the alpha component of the ciliary neurotrophic factor receptor complex, which is required to convert a functional leukemia inhibitory factor/oncostatin M receptor complex into a ciliary neurotrophic factor receptor complex. The recent observation that the alpha component of the ciliary neurotrophic factor receptor complex is expressed by very early neuronal precursors suggested that ciliary neurotrophic factor may act on even earlier precursors, particularly on cells previously thought to be targets for leukemia inhibitory factor action. Here we show the first example of ciliary neurotrophic factor responsiveness in cells residing outside of the nervous system by demonstrating that embryonic stem cells express a functional ciliary neurotrophic factor receptor complex, and that ciliary neurotrophic factor is similar to leukemia inhibitory factor in its ability to maintain the pluripotentiality of these cells.
TL;DR: It is proposed that NT-4, together with the other three neurotrophins, orchestrate the innervation of the different structures of the developing whisker pad by the trigeminal ganglion, acting as target-derived neurotrophic factors for different subpopulations of trigemINAL ganglions neurons.
Abstract: The cellular localization of mRNA for neurotrophin-4 (NT-4), a novel neurotrophic factor, in the developing whisker follicles and skin of the embryonic rat is demon strated by in situ hybridization. Levels of NT-4 mRNA in the whisker pad decrease between embryonic day 13 (E13) and E20, correlating in time with the onset of nat urally occurring neuronal death in the innervating trigeminal ganglion. In addition to NT-4, brain-derived neuotrophic factor (BDNF) mRNA is also shown to be expressed in the rat embryonic whisker follicles although in a different cellular localization, which com bined with previous data on the expression of NGF and NT-3 mRNAs, shows that all four neurotrophins are expressed during development of this structure. NT-4 protein is shown to elicit neurite outgrowth from explanted embryonic trigeminal ganglia and to promote neuronal survival of dissociated trigeminal ganglion neurons when cultured during the phase of cell death. NT-4 and NT-3 mainly support different neuronal subpopulations, whereas some NT-4-responsive cells appear to respond also to NGF and BDNF. Analysis of mRNAs for members of the Trk family of neurotrophin receptors in neurons rescued by different neurotrophins demonstrates the presence of distinct neuronal subpopulations that respond to specific combinations of these factors. Based on these results we propose that NT-4, together with the other three neurotrophins, orchestrate the innervation of the different structures of the devel oping whisker pad by the trigeminal ganglion, acting as target-derived neurotrophic factors for different subpopulations of trigeminal ganglion neurons. SUMMARY
TL;DR: Data show that the two known LIF receptor components are recruited by CNTF and CNTFR alpha to form a trimeric CNTF receptor complex, which was originally cloned as a LIF-binding protein.
Patent•
30 Jul 1993
TL;DR: In this article, a method of enhancing the differentiation of neuronal precursor cells into NGF-dependent neuronal cells, which method includes treating precursor cells with a combination of a member of the FGF family and a members of the CTNF family to enhance their effectiveness and survival in transplantation therapy for the treatment of diseases such as Parkinson's disease.
Abstract: Method of enhancing the differentiation of neuronal precursor cells into NGF-dependent neuronal cells, which method includes treating precursor cells with a combination of a member of the FGF family and a member of the CTNF family to enhance their effectiveness and survival in transplantation therapy for the treatment of diseases such as Parkinson's disease.
TL;DR: Although the neurotrophin and CNTF receptor systems differ drastically, they display certain parallels and both depend on ligand-induced dimerization of signal transducing receptor components to activate signaling.
Patent•
02 Sep 1993TL;DR: In this article, a novel dorsal growth inducing factors, complexes including the factors, and DNA or RNA coding sequences for the factors are described, as well as the complexes and the coding sequences of the factors.
Abstract: Novel dorsal growth inducing factors, complexes including the factors, and DNA or RNA coding sequences for the factors are described.
Patent•
01 Jul 1993TL;DR: In this paper, an assay system useful for detecting denervated or degenerating muscle by measuring the amount of soluble ciliary neurotrophic factor receptor in body fluids is described, which can be used to detect denervation or degeneration.
Abstract: An assay system useful for detecting denervated or degenerating muscle by measuring the amount of soluble ciliary neurotrophic factor receptor in body fluids is described.
Patent•
30 Jul 1993
TL;DR: In this article, a procede permet dameliorer the differentiation des cellules precurseurs neuronales en cellules neuronales dependantes du NGF (facteur de croissance des nerfs).
Abstract: Un procede permet d'ameliorer la differentiation des cellules precurseurs neuronales en cellules neuronales dependantes du NGF (facteur de croissance des nerfs). Ce procede consiste a traiter lesdites cellules precurseurs avec une combinaison d'un membre de la famille FGF (facteur de croissance des fibroblastes) et d'un membre de la famille CNTF (facteur neurotrophique ciliaire) pour renforcer leur efficacite et leur chances de survie dans une therapie de transplantation destinee au traitement de maladies telles que la maladie de Parkinson.