TY - JOUR A1 - Sendtner, Michael A1 - Arakawa, Yoshihiro A1 - Stöckli, Kurt A. A1 - Kreutzberg, Georg W. A1 - Thoenen, Hans T1 - Effect of ciliary neurotrophic factor (CNTF) on motoneuron survival N2 - 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. KW - motoneurons KW - ciliary neurotrophic factor KW - CNTF KW - nerve lesion KW - rat KW - chick KW - neurotrophic factor Y1 - 1991 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-33048 ER - TY - CHAP A1 - Thoenen, Hans A1 - Hughes, Richard A. A1 - Sendtner, Michael T1 - Towards a comprehensive understanding of the trophic support of motoneurons N2 - Motoneurons played an essential role in establishing the concept of target-mediated support of innervating neurons. However, it took several decades until molecules were identined which trophically support motoneurons in vitro and in vivo. The most potent molecule identined so far is ciliary neurotrophic factor (CNTF). It is expressed as a cytosolic molecule in myelinating Schwann cells rather than in skeletal muscle in the postnatal period and therefore does not qualify as a target-derived neurotrophic factor regulating motoneuron survival during embryonic development. However, the inactivation of CNTF by gene targeting experiments results in progressive atrophy and degeneration of motoneurons, demonstrating that CNTF plays an essential role as a maintenance factor for motoneurons postnatally. Secretory molecules which are expressed in skeletal muscle during embryonic development and which support motoneurons in culture and partially also in vivo include members of the NGF gene family (BDNF, NT-3, NT-4/S) , FGF-S, IGF-I, and UF. The evaluation of the physiological importance of these molecules is under investigation. KW - neurotrophic molecules KW - CNTF KW - gene targeting KW - NGF gene family KW - FGF-5 KW - lIF KW - IGF-I Y1 - 1993 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-31117 ER - TY - JOUR A1 - Sendtner, Michael A1 - Thoenen, Hans A1 - Hughes, R. A. T1 - Members of several gene families influence survival of rat motoneurons in vitro and in vivo N2 - The survival and functional maintenance of spinal motoneurons, both during the period of developmental cell death and in adulthood, have been shown to be dependent on trophic factors. In vitro experiments have previously been used to identify several survival factors for motoneurons, including CNTF, UF, and members of the neurotrophin, FGF, and IGF gene families. Some of these factors have also been shown to be active in vivo, either on chick motoneurons during embryonic development or on lesioned facial and spinal motoneurons of the newborn rat. Here we demonstrate that lesioned newborn rat facial motoneurons can be rescued by NT-4/5, IGF-I, and UF. Furthermore, in contrast to chick motoneurons, the survival of isolated embryonic rat motoneurons can be maintained by the neurotrophins BDNF, NT-3, and NT-4/5. IGF-I and FGF-5 were also active in this system, each supporting more than 50% of the originally plated neurons. The responsiveness of motoneurons to multiple factors in vitro and in vivo suggests that motoneuron survival and function are regulated by the coordinated actions of members of different gene families. KW - Immunopanning KW - Facial Nerve Transection KW - Neurotrophin KW - Fibroblast Growth Factor KW - Insulinlike Growth Factor Y1 - 1993 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-42652 ER - TY - JOUR A1 - Sendtner, Michael A1 - Thoenen, Hans A1 - Holtmann, B. A1 - Kohlbeck, R. A1 - Barde, Y.-A. T1 - Brain-derived neurotrophic factor prevents the death of motoneurons in newborn rats after nerve section N2 - 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. Y1 - 1992 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-42673 ER - TY - JOUR A1 - Sendtner, Michael A1 - Thoenen, Hans T1 - Oxidative stress and motorneuron disease N2 - Transgenic mice carrying mutated Cu/Zn superoxide dismutase genes provide insights into the pathogenesis of human motorneuron diseases and may be useful as models in the development and testing of therapies. Y1 - 1994 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-42684 ER - TY - JOUR A1 - Sendtner, Michael A1 - Stöckli, Kurt A. A1 - Carroll, Patrick A1 - Kreutzberg, Georg W. A1 - Thoenen, Hans T1 - More on motor neurons N2 - No abstract available Y1 - 1992 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-42598 ER - TY - JOUR A1 - Sendtner, Michael A1 - Gnahn, H. A1 - Wakade, A. A1 - Thoenen, Hans T1 - Is activation of the Na\(^+\)K\(^+\) pump necessary for NGF-mediated neuronal survival? N2 - The ability of nerve growth factor to cause rapid activation of the Na+K+ pump of its responsive cells was examined by measuring the uptake of 86Rb+. A significant increase in 86Rb+ uptake in Ea chick dorsal root ganglion sensory neurons after NGF treatment was seen only if the cells had been damaged during the preparation procedure. Such damaged cells could not survive in culture in the presence of NGF, and undamaged cells that did survive in response to NGF exhibited no increased 86Rb+ uptake rate. Furthermore, cultured calf adrenal medullary cells did not show an increase in 86Rb+ uptake after treatment with NGF, although these cells respond to NGF with an increased synthesis of catecholaminergic enzymes. These results are incompatible with the hypothesis that the mechanism of action of NGF that promotes neuronal survival and enzyme induction results from an initial stimulation of the Na+K+ pump. Y1 - 1988 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-42610 ER - TY - JOUR A1 - Dittrich, Falk A1 - Thoenen, Hans A1 - Sendtner, Michael T1 - Ciliary neurotrophic factor: pharmacokinetics and acute-phase response in rat N2 - No abstract available Y1 - 1994 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-42639 ER - TY - JOUR A1 - Dohrmann, Ulrike A1 - Edgar, David A1 - Sendtner, Michael A1 - Thoenen, Hans T1 - Muscle-derived factors that support survival and promote fiber outgrowth from embryonic chick spinal motor neurons in culture N2 - The purpose of the experiments reported is to provide an unambiguous demonstration that embryonie skeletal muscle contains factors that act directly on embryonie spinal motor neurons both to support their survival and to stimulate the outgrowth of neurites. Cells of lumbar and brachial ventral spinal cords from 6-day-old chick embryos were separated by centrifugation in a two-step metrizamide gradient, and a motor neuron enriched fraction was obtained. Motor neurons were identified by retrogradely labeling with rhodamine isothiocyanate, and were enriched fourfold in the motor neuron fraction relative to unfractionated cells. In culture, the isolated motor neurons died within 3-4 days unless they were supplemented with embryonie chick skeletal muscle extract. Two functionally distinct entities separable by ammonium sulfate precipitation were responsible for the effects of muscle extracts on motor neurons. The 0-25% ammonium sulfate precipitate contained molecules that alone bad no effect on neuronal survival but when bound to polyornithine-coated culture substrata, stimulated neurite outgrowth and potentiated the survival activity present in muscle. Most of this activity was due to a laminin-like molecule being immunoprecipitated with antisera against laminin, and immunoblotting demonstrated the presence of both the A and B chains of laminin. A long-term survival activity resided in the 25-70% ammonium sulfate fraction, and its apparent total and specific activities were strongly dependent on the culture substrate. In contrast to the motor neurons, the cells from the other metrizamide fraction (including neuronal cells) could be kept in culture for a prolonged time without addition of exogenous factor(s). KW - Nervenzelle Y1 - 1986 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-72862 ER -