Refine
Has Fulltext
- yes (61) (remove)
Is part of the Bibliography
- yes (61)
Year of publication
Document Type
- Journal article (56)
- Report (2)
- Review (2)
- Book article / Book chapter (1)
Language
- English (61) (remove)
Keywords
- amyotrophic lateral sclerosis (4)
- Neurotrophic factors (3)
- ciliary neurotrophic factor (3)
- spinal muscular atrophy (3)
- BDNF (2)
- CNTF (2)
- RNA (2)
- Schwann cells (2)
- TrkB (2)
- autophagy (2)
- motoneurons (2)
- neuromuscular junction (2)
- neurons (2)
- spinal cord (2)
- synaptic plasticity (2)
- 3D cell culture (1)
- Aging (1)
- Alzheimer's disease (1)
- Alzheimers disease (1)
- Alzheimer’s disease (1)
- Amyotrophic-lateral-sclerosis (1)
- Associative learning (1)
- Astrocytes ; Schwann cells ; Interferon-gamma ; Fibroblast growth factor ; Cyclic AMP (1)
- Axon degeneration (1)
- Axon growth (1)
- Axonal degeneration (1)
- Axonal transport (1)
- BDNF stimulation (1)
- BSTA (1)
- Brain (1)
- C. elegans (1)
- C9orf72 (1)
- Cells (1)
- DAPI staining (1)
- DNA repeat expansion (1)
- DRD1 (1)
- Diabetic polyneuropathy (1)
- Drosophilia (1)
- Exercise (1)
- FGF-5 (1)
- Facial Nerve Transection (1)
- Fear conditioning (1)
- Fibroblast Growth Factor (1)
- GPCR (1)
- Glutamatergic synapses (1)
- Hippocampus (1)
- IGF-I (1)
- Immunopanning (1)
- Insulinlike Growth Factor (1)
- Intermediate filaments (1)
- Lacking neurofilaments (1)
- MAP1B (1)
- Microtubules (1)
- Missense mutation (1)
- Molecular neuroscience (1)
- Motoneuron disease (1)
- Motor behaviour (1)
- Motor nerve biopsy (1)
- Motor neuron disease; Ciliary neurotrophic factor; Brain-derived neurotrophic factor; Animal models; Neurotrophic factors (1)
- Mouse model (1)
- Mus spretus (1)
- NGF gene family (1)
- NMJ–neuromuscular junction (1)
- Nervenzelle (1)
- Neurobiologie (1)
- Neurofilament (1)
- Neuropathy (1)
- Neurotrophin (1)
- Object recognition (1)
- PKB/Akt phosphorylation (1)
- PLEKHG5 (1)
- Phosphorylation (1)
- Plasma-membrane (1)
- Pleckstrin homology containing family member 5 (Plekhg5) (1)
- Progressive motor neuronopathy (1)
- Protein kinase B (1)
- RNA splicing (1)
- RNA transport (1)
- RNA-binding proteins (1)
- Rictor-mTOR complex (1)
- SAP47 gene (1)
- SMN (1)
- SMN granules (1)
- Spinal Muscular-arthropy (1)
- Stat3 (1)
- Stathmin (1)
- Syap1 knockout (1)
- Syap1 localization (1)
- Tdp-43 (1)
- Transcription (1)
- Transgenic mice (1)
- Vascular plasticity (1)
- Viability (1)
- YB-1 (1)
- actin messenger RNA (1)
- adenocarcinoma of the lung (1)
- apoptosis (1)
- axonal degeneration (1)
- axonal transcriptome (1)
- axons (1)
- basal ganglia (1)
- cerebral blood flow (1)
- chick (1)
- ciliary neuron (1)
- ciliary neurotrophic factor (CNTF) (1)
- ciliary-neurotrophic factor (1)
- comet assay (1)
- cortico-striatal synapse (1)
- cross-sectional studies (1)
- cytosol (1)
- dSPN (1)
- degeneration (1)
- demyelination (1)
- determining gene-product (1)
- direct pathway (1)
- dynamics of ribosomal assembly (1)
- early-onset predictors (1)
- electron tomography (1)
- enrichment (1)
- exercise (1)
- factor prevents (1)
- frontotemporal dementia (1)
- fused in sarcoma (1)
- gene targeting (1)
- genome wide (1)
- genome-wide association studies (1)
- hippocampus (1)
- homologous recombination (1)
- iPSC (induced pluripotent stem cells) (1)
- immune response (1)
- immunoprecipitation (1)
- injury (1)
- insulin (1)
- insulin-likegrowth factor I (1)
- interacts (1)
- interleukin 6 (1)
- interspeific backcross (1)
- lIF (1)
- linkage (1)
- lung and intrathoracic tumors (1)
- medicine (1)
- memory (1)
- metastasis (1)
- mild cognitive impairment (1)
- molecular neuroscience (1)
- motoneuron (1)
- motoneuron (MN) (1)
- motoneuron disease (1)
- motor axons (1)
- motor learning (1)
- motor neuron degeneration (1)
- mulitple-sclerosis patients (1)
- myelin (1)
- nerve lesion (1)
- neurofilaments (1)
- neuron migration (1)
- neurotrophic factor (1)
- neurotrophic molecules (1)
- neurotrophins (1)
- nicotinamide (1)
- non-small cell lung cancer (1)
- nonneuronaI cells (1)
- nuclear ribonucleoprotein-R (1)
- presynaptic ER dynamics (1)
- programmed cell death (1)
- protein interactions (1)
- rat (1)
- receptor (1)
- recombinant proteins (1)
- regulation (1)
- restriction fragment length polymorphism (1)
- secondary lung tumors (1)
- skeletal muscle (1)
- subcellular trafficking (1)
- survival (1)
- synaptic vesicles (1)
- thoracic diaphragm (1)
- transactivation (1)
- transcription-3 (STAT3) (1)
- uper-resolution array tomography (1)
- vector cloning (1)
- β-actin mRNA (1)
Institute
- Institut für Klinische Neurobiologie (58)
- Theodor-Boveri-Institut für Biowissenschaften (5)
- Neurologische Klinik und Poliklinik (4)
- Institut für Anatomie und Zellbiologie (3)
- Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie (2)
- Frauenklinik und Poliklinik (1)
- Institut für Psychologie (1)
- Lehrstuhl für Biochemie (1)
- Medizinische Klinik und Poliklinik II (1)
0-2A progenitor cells give rise to both oligodendrocytes and type-2 astrocytes in vitro. Whereas oligodendrocyte differentiation occurs constitutively, type-2 astrocyte differentiation requires extracellular signals, one of which is thought to be ciliary neurotrophic factor (CNTF). CNTF, however, is insufficient by itself to induce the development of stable type-2 astrocytes. In this report we show the following: (a) that molecules associated with the extracellular matrix (ECM) cooperate with CNTF to induce stable type-2 astrocyte differentiation in serumfree cultures. The combination of CNTF and the ECM-associated molecules thus mimics the effect of FCS, which has been shown previously to induce stable type-2 astrocyte differentiation in vitro. (b) Both the ECM-associated molecules and CNTF act directly on 0-2A progenitor cells and can induce them to differentiate prematurely into type-2 astrocytes. (c) ECM-associated molecules also inhibit oligodendrocyte differentiation, even in the absence of CNTF, but this inhibition is not sufficient on its own to induce type-2 astrocyte differentiation. (d) Whereas the effect of ECM on oligodendrocyte differentiation is mimicked by basic fibroblast growth factor (bFGF), the effect of ECM on type-2 astrocyte differentiation is not. (e) The ECM-associated molecules that are responsible for inhibitin~ oligodendrocyte differentiation and for cooperating with CNTF to induce type-2 astrocyte differentiation are made by non-glial cells in vitro. (f) Molecules that have these activities and bind to ECM are present in the optic nerve at the time type-2 astrocytes are thought to be developing.
Ciliary neurotrophic factor (CNTF) is a potent survival molecule for a variety of embryonic neurons in culture. The developmental expression of CNTF occurs clearly after the time period of the physiological cell death of CNTF-responsive neurons. This, together with the sites of expression, excludes CNTF as a target-derived neuronal survival factor, at least in rodents. However, CNTF also participates in the induction of type 2 astrocyte differentiation in vitro. Here we demonstrate that the time course of the expression of CNTF-mRNA and protein in the rat optic nerve (as evaluated by quantitative Northern blot analysis and biological activity, respectively) is compatible with such a glial differentiation function of CNTF in vivo. We also show that the type 2 astrocyte-inducing- activity previously demonstrated in optic nerve extract can be precipitated by an antiserum against CNTF. Immunohistochemical analysis of astrocytes in vitro and in vivo demonstrates that the expression of CNTF is confined to a subpopulation of type 1 astrocytes. The olfactory bulb of adult rats has comparably high levels of CNTF to the optic nerve, and here again, CNTF-immunoreactivity is localized in a subpopulation of astrocytes. However, the postnatal expression of CNTF in the olfactory bulb occurs later than in the optic nerve. In other brain regions both CNTF-mRNA and protein levels are much lower.
We have demonstrated that the extensive degeneration of motoneurons in the rat facial nucleus after transection of the facial nerve in newborn rats can be prevented by local ciliary neurotrophic factor (CNTF) administration. CNTF differs distinctly from known neurotrophic molecules such as NGF, BDNF and NT-3 in both its molecular characteristics (CNTF is a cytosolic rather than a secretory molecule) and its broad spectrum of biological activities. CNTF is expressed selectively by Schwann cells and astrocytes of the peripheral and central nervous system, respectively, but not by target tissues of the great variety of CNTF -responsive neurons. CNTF mRNA is not detectable by Northern blot or PCR analysis during embryonic development and immediately after birth. However, during the second post-natal week, a more than 30-fold increase in CNTF mRNA and pro tein occurs in the sciatic nerve. Since the period of low CNTF levels in peripheral nerves coincides with that of high vulnerability of motoneurons (i.e. axonallesion results in degeneration of motoneuron cell bodies), insufficient availability of CNTF may be the reason for the rate of lesioninduced cell death of early post-natal motoneurons. Highly enriched embryonic chick motoneurons in culture are supported at survival rates higher than 60% by CNTF, even in single cell cultures, indicating that CNTF acts directly on motoneurons. In contrast to CNTF, the members of the neurotrophin gene family (NGF, BDNF and NT-3) do not support the survival of motoneurons in culture. However, aFGF and bFGF show distinct survival activities which are additive to those of CNTF, resulting in the survival of virtually all motoneurons cultured in the presence of CNTF and bFGF.
The cDNA for ciliary neurotrophic factor (CNTF), a polypeptide involved in the survival of motoneurons in mammals, has recently been cloned (Stöckli et al., Nature, 342, 920 - 923, 1989; Lin et al. Science, 246, 1023 - 1025, 1989). We have now localized the corresponding gene Cntf to chromosome 19 in the mouse, using an interspecific cross between Mus spretus and Mus musculus domesticus. The latter was carrying the gene wobbler (wr) for spinal muscular atrophy. DNA was prepared from backcross individuals and typed for the segregation of species-specific Cntf restriction fragments in relation to DNA markers of known chromosomal location. The M.spretus allele of Cntf cosegregated with chromosome 19 markers and mapped closely to Ly-1, to a region of mouse chromosome 19 with conserved synteny to human chromosome 11q. Cntf is not linked to wr, and the expression of CNTF mRNA and protein appears close to normal in facial and sciatic nerves, of affected (wr/wr) mice, suggesting that motoneuron degeneration of wobbler mice has its origin in defects other than reduced CNTF expression.
Ciliary neurotrophic factor (CNTF) is expressed in high quantities in Schwann cells of peripheral nerves during postnatal development of the rat. The absence of a hydrophobic leader sequence and the immunohistochemical localization of CNTF within the cytoplasm of these cells indicate that the factor might not be available to responsive neurons under physiological conditions. However, CNTF supports the survival of a variety of embryonic neurons, including spinal motoneurons in culture. Moreover we have recently demonstrated that the exogenous application of CNTF protein to the lesioned facial nerve of the newborn rat rescued these motoneurons from cell death. These results indicate that CNTF might indeed play a major role in assisting the survival of lesioned neurons in the adult peripheral nervous system. Here we demonstrate that the CNTF mRNA and protein levels and the manner in which they are regulated are compatible with such a function in lesioned peripheral neurons. In particular, immunohistochemical analysis showed significant quantities of CNTF at extracellular sites after sciatic nerve lesion. Western blots and determination of CNTF biological activity of the same nerve segments indicate that extracellular CNTF seems to be biologically active. After nerve lesion CNTF mRNA levels were reduced to <5 % in distal regions of the sciatic nerve whereas CNTF bioactivity decreased to only one third of the original before-lesion levels. A gradual reincrease in Schwann cells occurred concomitant with regeneration.
CILIARY neurotrophic factor (CNTF) supports the survival of embryonic motor neurons in vitro and in vivo and prevents lesion-mediated degeneration of rat motor neuron~ during early post-natal stages. Here we report that CNTF greatly reduces all the functional and morphological changes in pmnlpmn mice5, an autosomal recessive mutant leading to progressive caudo-cranial motor neuron degeneration. The first manifestations of progressive motor neuronopathy in homozygous pmnl pmn mice become apparent in the hind limbs at the end of the third post-natal week and all the mice die up to 6 or 7 weeks after birth from respiratory paralysis. Treatment with CNTF prolongs- survival- and greatly Impoves motor function of these mice. Moreover, morphological manifestations, such as loss of motor axons in the phrenic nerve and degeneration of facial motor neurons, were greatly reduced by CNTF, although the treatment did not start until the first symptoms of the disease had already become apparent and substantial degenerative changes were already present. The protective and restorative effects of CNTF in this mouse mutant give new perspectives for the treatment of human degenerative motor neuron diseases with CNTF.
Motoneurons innervating the skeletal musculature were among the first neurons shown to require the presence of their target cells to develop appropriatelyl,2. But the characterization of molecules allowing motoneuron survival has been difficult. Ciliary neurotrophic factor prevents the death of motoneurons3-6, but its gene is not expressed during development7. Although the presence of a neurotrophin receptor on developing motoneurons8-1O has suggested a role for neurotrophins, none could be shown to promote motoneuron survival in vitro3. We report here that brainderived neurotrophic factor can prevent the death of axotomized motoneurons in newborn rats, suggesting a role for this neurotrophin for motoneuron survival in vivo.
More on motor neurons
(1992)
Motoneuron diseases represent a m&jor challenge to modern neurology, yet their clinical manifestations ware first described more than hundred years ago, and despite many studies the etiology of these diseases ramd,ns obscure with no effective treatments having been reported. Although progress has been made in establishing genetic linkage in the rare inherited for.ms of these diseases such as familial amyotrophic lateral scleriosisl , spinal mDscular atrophy and X-linked bulbo-spinal-mDscular atrophy, this new information has not yet affected therapeutic techniques. During the last few years several important steps have been taken concerning the physiological mechanisms involved in motoneuron survival during development, after lesion and in animal models of degenerative diseases, the molecular clOning of several new neurotrophic factors (brain-derived neurotrophic factor (BDNP), neurotrophin-3 and-4 (NT-3 and NT-4) and ciliary neurotrophic factor (CNTP)); the identification of a gene family of receptor molecules for same of these factors, progress in the understanding of the effects of polypeptide growth factors on muscle cell differentiation, neuronal sprouting (insulin-like growth factor-I and -11 (IGF-I and IGF-II), and in vitro motoneuronal survival (CNTF, IGF-I and -II and basic FGF). These findings have raised new hopes in that they could lead to a better understanding of the pathophysiological processes underlying these diseases, and that the pharmacological use of same of these newly characterized neurotrophic factors could present new possibilities for the treatment of these diseases.