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Jeffrey Milbrandt - One of the best experts on this subject based on the ideXlab platform.

  • Neurturin signalling via gfrα2 is essential for innervation of glandular but not muscle targets of sacral parasympathetic ganglion neurons
    Molecular and Cellular Neuroscience, 2004
    Co-Authors: Y Wanigasekara, Matti S Airaksinen, Robert O Heuckeroth, Jeffrey Milbrandt, Janet R. Keast
    Abstract:

    Neurturin, a member of the glial cell-derived neurotrophic factor familys of ligands, is important for development of many cranial parasympathetic ganglion neurons. We have investigated the sacral component of the parasympathetic nervous system in mice with gene deletions for Neurturin or its preferred receptor, GFRα2. Disruption of Neurturin signalling decreased cholinergic VIP innervation to the mucosa of the reproductive organs, but not to the smooth muscle layers of these organs or to the urinary bladder. Thus, Neurturin and its receptor are involved in parasympathetic innervation of a select group of pelvic visceral tissues. In contrast, noradrenergic innervation was not affected by the gene ablations. The epithelium of reproductive organs from knockout animals was atrophied, indicating that cholinergic innervation may be important for the maintenance of normal structure. Cholinergic neurons express GFRα2 on their terminals and somata, indicating they can respond to neurotrophic support, and their somata are smaller when Neurturin signalling is disrupted. Colocalisation studies showed that many peripheral glia express GFRα2 although its role in these cells is yet to be determined. Our results indicate that Neurturin, acting through GFRα2, is essential for parasympathetic innervation of the mucosae of reproductive organs, as well as for maintenance of a broader group of sacral parasympathetic neurons.

  • Neurturin deficient mice develop dry eye and keratoconjunctivitis sicca
    Investigative Ophthalmology & Visual Science, 2003
    Co-Authors: Xiu Jun Song, Robert O Heuckeroth, Jeffrey Milbrandt, William J Farley, Li Hui Luo, Stephen C Pflugfelder
    Abstract:

    PURPOSE: Neurturin has been identified as a neurotrophic factor for parasympathetic neurons. Neurturin-deficient (NRTN(-/-)) mice have defective parasympathetic innervation of their lacrimal glands. This study was conducted to evaluate tear function and ocular surface phenotype in NRTN(-/-) mice. METHODS: Determined by tail genomic DNA PCR, 25 NRTN(-/-) mice and 17 Neurturin-normal (NRTN(+/+)) mice aged 6 weeks to 4 months were evaluated. Aqueous tear production, tear fluorescein clearance and corneal sensation were serially measured. Corneal permeability to AlexaFluor dextran (AFD; Molecular Probes, Eugene, OR) was measured by a fluorometric assay at 485 nm excitation and 530 nm emission. Histology was evaluated in PAS-stained sections. Mucin and HLA class II (IA) antigen were assessed by immunofluorescent staining. Tear IL-1beta was measured by ELISA, and tear matrix metalloproteinase (MMP)-9 by zymography. Gene expression in the corneal epithelia was analyzed by semiquantitative RT-PCR. RESULTS: In comparison to that in age-matched NRTN(+/+) mice, aqueous tear production, tear fluorescein clearance, and corneal sensation were significantly reduced in NRTN(-/-) mice, whereas corneal permeability to AFD was significantly increased. Immunoreactive MUC-4 and -5AC mucin and goblet cell density (P < 0.001) in the conjunctiva of NRTN(-/-) mice were lower than in NRTN(+/+) mice. The expression of MUC-1 and -4 mRNA by the corneal epithelium was reduced in NRTN(-/-) mice. There were a significantly greater number of IA antigen-positive conjunctival epithelial cells in NRTN(-/-) mice than NRTN(+/+) mice. Tear fluid IL-1beta and MMP-9 concentrations and the expression of IL-1beta, TNF-alpha, macrophage inflammatory protein (MIP)-2, cytokine-induced neutrophil chemoattractant (KC), and MMP-9 mRNA by the corneal epithelia were significantly increased in NRTN(-/-) mice, compared with NRTN(+/+) mice. CONCLUSIONS: Neurturin-deficient mice show phenotypic changes and ocular surface inflammation that mimic human keratoconjunctivitis sicca. This model supports the importance of a functional ocular surface-central nervous system-lacrimal gland sensory-autonomic neural network in maintaining ocular surface health and homeostasis.

  • gfrα mediated localization of ret to lipid rafts is required for effective downstream signaling differentiation and neuronal survival
    Neuron, 2000
    Co-Authors: Malú G. Tansey, Jeffrey Milbrandt, Robert H. Baloh, Eugene M. Johnson
    Abstract:

    The GDNF family ligands (GFLs: GDNF, Neurturin, persephin, and artemin) signal through RET and a gly-cosyl-phosphatidylinositol (GPI)-anchored coreceptor (GFRalpha1-alpha4) that binds ligand with high affinity and provides specificity. The importance of the GPI anchor is not fully understood; however, GPI-linked proteins cluster into lipid rafts, structures that may represent highly specialized signaling organelles. Here, we report that GPI-anchored GFRalpha1 recruits RET to lipid rafts after GDNF stimulation and results in RET/Src association. Disruption of RET localization using either transmembrane-anchored or soluble GFRalpha1 results in RET phosphorylation, but GDNF-induced intracellular signaling events are markedly attenuated as are neuronal differentiation and survival responses. Therefore, proper membrane localization of RET via interaction with a raft-localized, GPI-linked coreceptor is of fundamental importance in GFL signaling.

  • functional mapping of receptor specificity domains of glial cell line derived neurotrophic factor gdnf family ligands and production of gfrα1 ret specific agonists
    Journal of Biological Chemistry, 2000
    Co-Authors: Robert H. Baloh, Malú G. Tansey, Eugene M. Johnson, Jeffrey Milbrandt
    Abstract:

    Abstract The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) (GDNF, Neurturin, artemin, and persephin) are critical regulators of neurodevelopment and support the survival of midbrain dopaminergic and spinal motor neurons in vitro and in animal disease models making them attractive therapeutic candidates for treatment of neurodegenerative diseases. The GFLs signal through a multicomponent receptor complex comprised of a high affinity binding component (GDNF-family receptor α-component (GFRα1-GFRα4)) and the receptor tyrosine kinase RET. To begin characterization of GFL receptor specificity at the molecular level, we performed comprehensive homologue-scanning mutagenesis of GDNF, the prototypical member of the GFLs. Replacing short segments of GDNF with the homologous segments from persephin (PSPN) (which cannot bind or activate GFRα1·RET or GFRα2·RET) identified sites along the second finger of GDNF critical for activating the GFRα1·RET and GFRα2·RET receptor complexes. Furthermore, introduction of these regions from GDNF, Neurturin, or artemin into PSPN demonstrated that they are sufficient for activating GFRα1·RET, but additional determinants are required for interaction with the other GFRαs. This difference in the molecular basis of GFL-GFRα specificity allowed the production of GFRα1·RET-specific agonists and provides a foundation for understanding of GFL-GFRα·RET signaling at the molecular level.

  • the gdnf family ligands and receptors implications for neural development
    Current Opinion in Neurobiology, 2000
    Co-Authors: Robert H. Baloh, Hideki Enomoto, Eugene M. Johnson, Jeffrey Milbrandt
    Abstract:

    The glial cell line derived neurotrophic factor (GDNF) family has recently been expanded to include four members, and the interactions between these neurotrophic factors and their unique receptor system is now beginning to be understood. Furthermore, analysis of mice lacking the genes for GDNF, Neurturin, and their related receptors has confirmed the importance of these factors in neurodevelopment. The results of such analyses reveal numerous similarities and potential overlaps in the way the GDNF and the nerve growth factor (NGF) families regulate development of the peripheral nervous system.

Robert D Klein - One of the best experts on this subject based on the ideXlab platform.

  • Neurturin enhances the recovery of erectile function following bilateral cavernous nerve crush injury in the rat.
    Journal of brachial plexus and peripheral nerve injury, 2007
    Co-Authors: Anthony J Bella, Thomas M. Fandel, Kavirach Tantiwongse, William O. Brant, Robert D Klein, Carlos A Garcia, Tom F. Lue
    Abstract:

    Background The molecular mechanisms responsible for the survival and preservation of function for adult parasympathetic ganglion neurons following injury remain incompletely understood. However, advances in the neurobiology of growth factors, neural development, and prevention of cell death have led to a surge of clinical interest for protective and regenerative neuromodulatory strategies, as surgical therapies for prostate, bladder, and colorectal cancers often result in neuronal axotomy and debilitating loss of sexual function or continence. In vitro studies have identified Neurturin, a glial cell line-derived neurotrophic factor, as a neuromodulator for pelvic cholinergic neurons. We present the first in vivo report of the effects of Neurturin upon the recovery of erectile function following bilateral cavernous nerve crush injury in the rat.

  • Neurturin enhances the recovery of erectile function following bilateral cavernous nerve crush injury in the rat
    Journal of Brachial Plexus and Peripheral Nerve Injury, 2007
    Co-Authors: Anthony J Bella, Thomas M. Fandel, Kavirach Tantiwongse, William O. Brant, Robert D Klein, Carlos A Garcia
    Abstract:

    Background The molecular mechanisms responsible for the survival and preservation of function for adult parasympathetic ganglion neurons following injury remain incompletely understood. However, advances in the neurobiology of growth factors, neural development, and prevention of cell death have led to a surge of clinical interest for protective and regenerative neuromodulatory strategies, as surgical therapies for prostate, bladder, and colorectal cancers often result in neuronal axotomy and debilitating loss of sexual function or continence. In vitro studies have identified Neurturin, a glial cell line-derived neurotrophic factor, as a neuromodulator for pelvic cholinergic neurons. We present the first in vivo report of the effects of Neurturin upon the recovery of erectile function following bilateral cavernous nerve crush injury in the rat. Methods In these experiments, groups (n = 8 each) consisted of uninjured controls and animals treated with injection of albumin (blinded crush control group), extended release neurotrophin-4 or Neurturin to the site of cavernous nerve crush injury (100 μg per animal). After 5 weeks, recovery of erectile function (treatment effect) was assessed by cavernous nerve electrostimulation and peak aortic pressures were measured. Investigators were unblinded to specific treatments after statistical analyses were completed. Results Erectile dysfunction was not observed in the sham group (mean maximal intracavernous pressure [ICP] increase of 117.5 ± 7.3 cmH_2O), whereas nerve injury and albumin treatment (control) produced a significant reduction in ICP elevation of 40.0 ± 6.3 cmH_2O. Neurturin facilitated the preservation of erectile function, with an ICP increase of 55% at 62.0 ± 9.2 cmH_2O (p < 0.05 vs control). Extended release neurotrophin-4 did not significantly enhance recovery of erectile function with an ICP change of 46.9 ± 9.6. Peak aortic blood pressures did not differ between groups. No significant pre- and post-treatment weight differences were observed between control, neurotrophin-4 and Neurturin cohorts. All animals tolerated the five-week treatment course. Conclusion Treatment with Neurturin at the site of cavernous nerve crush injury facilitates recovery of erectile function. Results support further investigation of Neurturin as a neuroprotective and/or neuroregenerative agent facilitating functional recovery after cavernous or other pelvic autonomic nerve injuries.

  • Journal of Brachial Plexus and Peripheral Nerve Injury
    2006
    Co-Authors: Biomed Central, Anthony J Bella, Kavirach Tantiwongse, William O. Brant, Robert D Klein, Carlos A Garcia, Tom F. Lue, Thomas M F
    Abstract:

    Research article Neurturin enhances the recovery of erectile function following bilateral cavernous nerve crush injury in the ra

  • a gpi linked protein that interacts with ret to form a candidate Neurturin receptor
    Nature, 1997
    Co-Authors: Robert D Klein, Daniel Eric Sherman, Weihsien Ho, Donna M Stone, Gregory L Bennett, Barbara Moffat, Richard Vandlen, Laura Simmons, Qimin Gu
    Abstract:

    Glial-cell-line-derived neurotrophic factor (GDNF) and Neurturin (NTN) are two structurally related, potent survival factors for sympathetic, sensory and central nervous system neurons1,2,3,4,5,6. GDNF mediates its actions through a multicomponent receptor system composed of a ligand-binding glycosyl-phosphatidylinositol (GPI)-linked protein (designated GDNFR-α) and the transmembrane protein tyrosine kinase Ret7,8,9,10,11,12. In contrast, the mechanism by which the NTN signal is transmitted is not well understood. Here we describe the identification and tissue distribution of a GPI-linked protein (designated NTNR-α) that is structurally related to GDNFR-α. We further demonstrate that NTNR-α binds NTN (Kd ∼ 10 pM) but not GDNF with high affinity; that GDNFR-α binds to GDNF but not NTN with high affinity; and that cellular responses to NTN require the presence of NTNR-α. Finally, we show that NTN, in the presence of NTNR-α, induces tyrosine-phosphorylation of Ret, and that NTN, NTNR-α and Ret form a physical complex on the cell surface. These findings identify Ret and NTNR-α as signalling and ligand-binding components, respectively, of a receptor for NTN and define a novel family of receptors for neurotrophic and differentiation factors composed of a shared transmembrane protein tyrosine kinase and a ligand-specific GPI-linked protein.

Eugene M. Johnson - One of the best experts on this subject based on the ideXlab platform.

  • post mortem assessment of the short and long term effects of the trophic factor Neurturin in patients with α synucleinopathies
    Neurobiology of Disease, 2015
    Co-Authors: Raymond T Bartus, Jeffrey H Kordower, Eugene M. Johnson, Tiffany L Baumann, Lamar Brown, Brian Kruegel, Anthony E Lang, C W Olanow, Christopher D Herzog
    Abstract:

    Abstract Substantial interest persists for developing neurotrophic factors to treat neurodegenerative diseases. At the same time, significant progress has been made in implementing gene therapy as a means to provide long-term expression of bioactive neurotrophic factors to targeted sites in the brain. Nonetheless, to date, no double-blind clinical trial has achieved positive results on its primary endpoint despite robust benefits achieved in animal models. A major issue with advancing the field is the paucity of information regarding the expression and effects of neurotrophic factors in human neurodegenerative brain, relative to the well-characterized responses in animal models. To help fill this information void, we examined post-mortem brain tissue from four patients with nigrostriatal degeneration who had participated in clinical trials testing gene delivery of Neurturin to the putamen of patients. Each had died of unrelated causes ranging from 1.5-to-3-months (2 Parkinson's disease patients), to 4+-years (1 Parkinson's disease and 1 multiple-system atrophy-parkinsonian type patient) following gene therapy. Quantitative and immunohistochemical evaluation of Neurturin, alpha-synuclein, tyrosine hydroxylase (TH) and an oligodendroglia marker (Olig 2) were performed in each brain. Comparable volumes-of-expression of Neurturin were seen in the putamen in all cases (~ 15–22%; mean = 18.5%). TH-signal in the putamen was extremely sparse in the shorter-term cases. A 6-fold increase was seen in longer-term cases, but was far less than achieved in animal models of nigrostriatal degeneration with similar or even far less NRTN exposure. Less than 1% of substantia nigra (SN) neurons stained for Neurturin in the shorter-term cases. A 15-fold increase was seen in the longer-term cases, but Neurturin was still only detected in ~ 5% of nigral cells. These data provide unique insight into the functional status of advanced, chronic nigrostriatal degeneration in human brain and the response of these neurons to neurotrophic factor stimulation. They demonstrate mild but persistent expression of gene-mediated Neurturin over 4-years, with an apparent, time-related amplification of its transport and biological effects, albeit quite weak, and provide unique information to help plan and design future trials.

  • bioactivity of aav2 Neurturin gene therapy cere 120 differences between parkinson s disease and nonhuman primate brains
    Movement Disorders, 2011
    Co-Authors: Raymond T Bartus, Eugene M. Johnson, Warren C Olanow, Joao Siffert, Lamar Brown, Christopher D Herzog, Yaping Chu, Alistair Wilson, Elliott J Mufson, Jeffrey H Kordower
    Abstract:

    Background: AAV2-Neurturin (CERE- 120) is designed to deliver the neurotrophic-factor, neu- rturin, to the striatum to restore and protect degenerat- ing nigrostriatal neurons in Parkinson's disease (PD). A common hypothesis is that following expression in the striatum, neurotrophic-factors like Neurturin (NRTN) will be transported from degenerating terminals to their cell bodies in the substantia nigra pars compacta (SNc). Methods: We tested this concept using immunohisto- chemistry, comparing the bioactivity of AAV2-Neurturin in brains of PD patients versus those of nonhuman pri- mates similarly treated. Results: NRTN-immunostaining in the targeted striatum was seen in all PD cases (mean putaminal coverage: ~15% by volume); comparable expression was observed in young, aged, and parkinsonian monkeys. In the SNc cell bodies, however, only rare evidence of Neurturin was seen in PD, while ample evidence of intense nigral-NRTN was observed in all monkeys. NRTN-expression was associated with occasional, sparse TH-induction in the striatum of PD, but nothing apparent in the SNc. In primates, NRTN produced ro- bust TH-induction throughout the nigrostriatal neurons. Discussion: These data provide the first evidence that gene therapy can increase expression of a neurotrophic- factor deep in the PD brain and that clear but modest enhancement of degenerating neurons can be induced. They also provide important insight regarding deficiencies in the status of nigrostriatal neurons in advanced PD, sug- gesting that serious axon-transport deficits reduced the bioactivity of AAV2-NRTN by limiting the protein exposed to the cell body. Thus, future efforts using neurotrophic- factors to treat neurodegenerative diseases will need to target both the terminal fields and the cell bodies of degenerating neurons to assure maximal benefit is achieved. V C 2010 Movement Disorder Society

  • c-Src is required for glial cell line-derived neurotrophic factor (GDNF) family ligand-mediated neuronal survival via a phosphatidylinositol-3 kinase (PI-3K)dependent pathway
    2001
    Co-Authors: Mario Encinas, Malú G. Tansey, Joan X Comella, Brian A. Tsui-pierchala, Jeffrey Milbr, Eugene M. Johnson
    Abstract:

    The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs), consisting of GDNF, Neurturin, persephin, and artemin, signal via a multicomponent complex composed of Ret tyrosine kinase and the glycosyl-phosphatidylinositol (GPI)anchored coreceptors GFR�1–�4. In previous work we have demonstrated that the localization of Ret to membrane microdomains known as lipid rafts is essential for GDNF-induced downstream signaling, differentiation, and neuronal survival. Moreover, we have found that Ret interacts with members of the Src family kinases (SFK) only when it is localized to these microdomains. In the present work we show by pharmacological and genetic approaches that Src activity was necessary to elicit optimal GDNF-mediated signaling, neurite outgrowth, and survival. In particular, p60Src, but not the other ubiquitous SFKs, Fyn and Yes, was responsible for the observed effects

  • gfrα mediated localization of ret to lipid rafts is required for effective downstream signaling differentiation and neuronal survival
    Neuron, 2000
    Co-Authors: Malú G. Tansey, Jeffrey Milbrandt, Robert H. Baloh, Eugene M. Johnson
    Abstract:

    The GDNF family ligands (GFLs: GDNF, Neurturin, persephin, and artemin) signal through RET and a gly-cosyl-phosphatidylinositol (GPI)-anchored coreceptor (GFRalpha1-alpha4) that binds ligand with high affinity and provides specificity. The importance of the GPI anchor is not fully understood; however, GPI-linked proteins cluster into lipid rafts, structures that may represent highly specialized signaling organelles. Here, we report that GPI-anchored GFRalpha1 recruits RET to lipid rafts after GDNF stimulation and results in RET/Src association. Disruption of RET localization using either transmembrane-anchored or soluble GFRalpha1 results in RET phosphorylation, but GDNF-induced intracellular signaling events are markedly attenuated as are neuronal differentiation and survival responses. Therefore, proper membrane localization of RET via interaction with a raft-localized, GPI-linked coreceptor is of fundamental importance in GFL signaling.

  • functional mapping of receptor specificity domains of glial cell line derived neurotrophic factor gdnf family ligands and production of gfrα1 ret specific agonists
    Journal of Biological Chemistry, 2000
    Co-Authors: Robert H. Baloh, Malú G. Tansey, Eugene M. Johnson, Jeffrey Milbrandt
    Abstract:

    Abstract The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) (GDNF, Neurturin, artemin, and persephin) are critical regulators of neurodevelopment and support the survival of midbrain dopaminergic and spinal motor neurons in vitro and in animal disease models making them attractive therapeutic candidates for treatment of neurodegenerative diseases. The GFLs signal through a multicomponent receptor complex comprised of a high affinity binding component (GDNF-family receptor α-component (GFRα1-GFRα4)) and the receptor tyrosine kinase RET. To begin characterization of GFL receptor specificity at the molecular level, we performed comprehensive homologue-scanning mutagenesis of GDNF, the prototypical member of the GFLs. Replacing short segments of GDNF with the homologous segments from persephin (PSPN) (which cannot bind or activate GFRα1·RET or GFRα2·RET) identified sites along the second finger of GDNF critical for activating the GFRα1·RET and GFRα2·RET receptor complexes. Furthermore, introduction of these regions from GDNF, Neurturin, or artemin into PSPN demonstrated that they are sufficient for activating GFRα1·RET, but additional determinants are required for interaction with the other GFRαs. This difference in the molecular basis of GFL-GFRα specificity allowed the production of GFRα1·RET-specific agonists and provides a foundation for understanding of GFL-GFRα·RET signaling at the molecular level.

Norio Kaneda - One of the best experts on this subject based on the ideXlab platform.

  • establishment and characterization of a noradrenergic adrenal chromaffin cell line tsam5ne immortalized with the temperature sensitive sv40 t antigen
    Cell Biology International, 2011
    Co-Authors: Susumu Kohno, Tomiyasu Murata, Kiyomi Hikita, Naoshi Koide, Norio Kaneda
    Abstract:

    We established a clonal adrenal medullary cell line, named tsAM5NE, from transgenic mice harbouring the temperature-sensitive Simian virus 40 large T-antigen gene, under the control of the tyrosine hydroxylase promoter. tsAM5NE cells conditionally grew at a permissive temperature of 33°C and exhibited the noradrenergic chromaffin cell phenotype. To understand the characteristics of tsAM5NE cells, we first examined the responsiveness of the cells to ligands of the GDNF (glial cell line-derived neurotrophic factor) family. tsAM5NE cells proliferated at the permissive temperature of 33°C in response to either GDNF or Neurturin, but not artemin or persephin. At the non-permissive temperature of 39°C, GDNF or Neurturin caused tsAM5NE cells to differentiate into neuron-like cells; however, the differentiated cells died in a time-dependent manner. Interestingly, LIF (leukaemia inhibitory factor) did not affect the GDNF-mediated cell proliferation at 33°C, but promoted the survival and differentiation of GDNF-treated cells at 39°C. In the presence of GDNF plus LIF, the morphological change induced by the temperature shift was associated with up-regulated expression of neuronal markers, indicating that the cells had indeed undergone neuronal differentiation. Thus, we demonstrated that tsAM5NE cells had the capacity to terminally differentiate into neuron-like cells in response to GDNF plus LIF when the oncogene was inactivated by the temperature shift. Thus, this cell line provides a useful model system for studying the mechanisms regulating neuronal differentiation.

  • neuronal differentiation elicited by glial cell line derived neurotrophic factor and ciliary neurotrophic factor in adrenal chromaffin cell line tsam5d immortalized with temperature sensitive sv40 t antigen
    Journal of Neuroscience Research, 2008
    Co-Authors: Tomiyasu Murata, Masaru Tsuboi, Kiyomi Hikita, Susumu Kohno, Naoshi Koide, Norio Kaneda
    Abstract:

    To understand the characteristics of tsAM5D cells immortalized with the temperature-sensitive simian virus 40 large T-antigen, we first examined the responsiveness of the cells to ligands of the glial cell line-derived neurotrophic factor (GDNF) family. tsAM5D cells proliferated at the permissive temperature of 33 degrees C in response to either GDNF or Neurturin, but not persephin or artemin. At the nonpermissive temperature of 39 degrees C, GDNF or Neurturin caused tsAM5D cells to differentiate into neuron-like cells; however, the differentiated cells died in a time-dependent manner. Interestingly, ciliary neurotrophic factor (CNTF) did not affect the GDNF-mediated cell proliferation at 33 degrees C but promoted the survival and differentiation of GDNF-treated cells at 39 degrees C. In the presence of GDNF plus CNTF, the morphological change induced by the temperature shift was associated with up-regulated expression of various neuronal marker genes, indicating that the cells had undergone neuronal differentiation. In addition, tsAM5D cells caused to differentiate by GDNF plus CNTF at 39 degrees C became dependent solely on nerve growth factor (NGF) for their survival and neurite outgrowth. Moreover, upon treatment with GDNF plus CNTF, the dopaminergic phenotype was suppressed by the temperature shift. Thus, we demonstrated that tsAM5D cells had the capacity to differentiate terminally into neuron-like cells in response to GDNF plus CNTF when the oncogene was inactivated by the temperature shift. This cell line provides a useful model system for studying the role of a variety of signaling molecules for GDNF/CNTF-induced neuronal differentiation.

Catherine Lubetzki - One of the best experts on this subject based on the ideXlab platform.

  • Ciliary neurotrophic factor (CNTF) enhances myelin formation: a novel role for CNTF and CNTF-related molecules.
    Journal of Neuroscience, 2002
    Co-Authors: Bruno Stankoff, Marie-stéphane Aigrot, Frédéric Noël, Aurélie Wattilliaux, Bernard Zalc, Catherine Lubetzki
    Abstract:

    In multiple sclerosis, myelin repair is generally insufficient despite the relative survival of oligodendrocytes within the plaques and the recruitment of oligodendrocyte precursors. Promoting remyelination appears to be a crucial therapeutic challenge. Using a newly developed enzymatic index of myelination, we screened different neurotrophic factors for their ability to enhance myelination. Neurotrophins [NGF, neurotrophin-3 (NT-3), NT-4/5, BDNF], glial cell line-derived neurotrophic factor (GDNF)-related factors (GDNF, Neurturin), and growth factors such as PDGF-AA, FGF-2, and insulin did not increase myelinogenesis. In contrast, among factors belonging to the CNTF family, CNTF, leukemia inhibitory factor, cardiotrophin-1, and oncostatin M induced a strong promyelinating effect. We provide evidence that CNTF acts on oligodendrocytes by favoring their final maturation, and that this effect is mediated through the 130 kDa glycoprotein receptor common to the CNTF family and transduced through the Janus kinase pathway. Our results demonstrate a novel role for neurotrophic factors of the CNTF family and raise the possibility that these factors might be of therapeutic interest to promote remyelination in multiple sclerosis.

  • Ciliary neurotrophic factor (CNTF) enhances myelin formation: a novel role for CNTF and CNTF-related molecules
    2002
    Co-Authors: Bruno Stankoff, Marie-stéphane Aigrot, Frédéric Noël, Aurélie Wattilliaux, Bernard Zalc, Catherine Lubetzki
    Abstract:

    In multiple sclerosis, myelin repair is generally insufficient despite the relative survival of oligodendrocytes within the plaques and the recruitment of oligodendrocyte precursors. Promoting remyelination appears to be a crucial therapeutic challenge. Using a newly developed enzymatic index of myelination, we screened different neurotrophic factors for their ability to enhance myelination. Neurotrophins [NGF, neurotrophin-3 (NT-3), NT-4/5, BDNF], glial cell line-derived neurotrophic factor (GDNF)-related factors (GDNF, Neurturin), and growth factors such as PDGF-AA, FGF-2, and insulin did not increase myelinogenesis. In contrast, among factors belonging to the CNTF family, CNTF, leukemia inhibitory factor, cardiotrophin-1, and oncostatin M induced a strong promyelinating effect. We provide evidence that CNTF acts on oligodendrocytes by favoring their final maturation, and that this effect is mediated throug