@article{StoeckliLottspeichSendtneretal.1989, author = {St{\"o}ckli, K. A. and Lottspeich, F. and Sendtner, Michael and Masiakowski, P. and Carroll, Patrick and G{\"o}tz, Rudolf and Lindholm, D. and Thoenen, Hans}, title = {Molecular cloning, expression and regional distribution of rat ciliary neurotrophic factor}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-34229}, year = {1989}, abstract = {CILIARY neurotrophic factor (CNTF) was originally characterized as a survival factor for chick ciliary neurons in vitro. More recently, it was shown to promote the survival of a variety of otherneuronal cell types and to affect the differentiation of E7 chick sympathetic neurons by inhibiting their proliferation and by inducing the expression of yasoactiYe intestinal peptide immunoreactiyity (VIP-IR). In cultures of dissociated sympathetic neurons from newborn rats, CNTF induces cholinergic differentiation as shown by increased levels of choline acetyltransferase (ChAT.}, language = {en} } @article{MengSendtnerSmith1995, author = {Meng, Li and Sendtner, Michael and Smith, Austin}, title = {Essential function of LIF receptor in motor neurons}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-34219}, year = {1995}, abstract = {D EVELOPME'iT and maintenance of the mammalian nervous system is dependent upon neurotrophic cytokines. One class of neurotrophic factor acts through rcccptor complexes involving the lowaffinity leukaemia inhibitor y faclor receptor subunit (LlF-R). Members of this fa mily of cytokines, such as ciliary neurotrophic factor (CNTF) and leukaemia inhibitory factor (LIF), have profound effects on the survival and maintenance of motor neurons, Recently it was reported that mice lacking LlF-R die shortly after birth unlike mice lacking CNTF or LIF which are viable. Here we describe histopathological analyses of lifr mutants tha t reveal a loss > 35\% of facia l motor neurons, 40\% of spinal motor neurons and 50\% of neurons in the nucleus ambiguus. These findings point to the existence of a ligand for LIF-R tha t is required for the normal development of motor neurons in both brainstem nuclei and spinal cord.}, language = {en} } @article{MasuWolfHoltmannetal.1993, author = {Masu, Yasuo and Wolf, Eckhard and Holtmann, Bettina and Sendtner, Michael and Brem, Gottfried and Thoenen, Hans}, title = {Disruption of the CNTF gene results in motor neuron degeneration}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-33038}, year = {1993}, abstract = {CNTF is a cytosolic molecule expressed postnatally in myelinating Schwann cells and in a subpopulation of astrocytes. Although CNTF administration prevents lesion-mediated and genetically determined motor neuron degeneration, its physiological function remained elusive. Here it is reported that abolition of CNTF gene expression by homologous recombination results in a progressive atrophy and loss of motor neurons in adult mice, which is functionally reflected by a small but significant reduction in muscle strength.}, language = {en} } @article{StoeckliLililienNaeherNoeetal.1991, author = {St{\"o}ckli, K. A. and Lililien, L. E. and N{\"a}her- No{\´e}, M. and Breitfeld, G. and Hughes, Richard A. and Raff, M. C. and Thoenen, Hans and Sendtner, Michael}, title = {Regional distribution, developmental changes, and cellular localization of CNTF-mRNA and protein in the rat brain}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-31172}, year = {1991}, abstract = {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.}, language = {en} } @article{SendtnerStoeckliThoenen1992, author = {Sendtner, Michael and St{\"o}ckli, K. A. and Thoenen, Hans}, title = {Synthesis and localization of ciliary neurotrophic factor in the sciatic nerve of the adult rat after lesion and during regeneration}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-31738}, year = {1992}, abstract = {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.}, language = {en} } @misc{ThoenenHughesSendtner1993, author = {Thoenen, Hans and Hughes, Richard A. and Sendtner, Michael}, title = {Trophic support of motoneurons: physiological, pathophysiological, and therapeutic implications.}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-31746}, year = {1993}, abstract = {No abstract available}, language = {en} } @techreport{SendtnerKreutzbergJennekens1992, author = {Sendtner, Michael and Kreutzberg, Georg W. and Jennekens, Frans G.}, title = {Workshop on trophic factors in the peripheral nervous system. Capri, October 1991.}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-31451}, year = {1992}, abstract = {No abstract available}, language = {en} } @article{ArakawaSendtnerThoenen1990, author = {Arakawa, Yoshihiro and Sendtner, Michael and Thoenen, Hans}, title = {Survival effect of ciliary neurotrophic factor (CNTF) on chick embryonic motoneurons in culture: comparison with other neurotrophic factors and cytokines}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-31718}, year = {1990}, abstract = {No abstract available}, language = {en} } @article{LillienSendtnerRohreretal.1988, author = {Lillien, Laura E. and Sendtner, Michael and Rohrer, Hermann and Hughes, Simon M. and Raff, Martin C.}, title = {Type-2 Astrocyte Development in Rat Brain Cultures is initiated by a CNTF-like protein produced by type-1 astrocytes}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-31708}, year = {1988}, abstract = {No abstract available}, language = {en} } @article{DombertSivadasanSimonetal.2014, author = {Dombert, Benjamin and Sivadasan, Rajeeve and Simon, Christian M. and Jablonka, Sibylle and Sendtner, Michael}, title = {Presynaptic Localization of Smn and hnRNP R in Axon Terminals of Embryonic and Postnatal Mouse Motoneurons}, doi = {10.1371/journal.pone.0110846}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-113655}, year = {2014}, abstract = {Spinal muscular atrophy (SMA) is caused by deficiency of the ubiquitously expressed survival motoneuron (SMN) protein. SMN is crucial component of a complex for the assembly of spliceosomal small nuclear ribonucleoprotein (snRNP) particles. Other cellular functions of SMN are less characterized so far. SMA predominantly affects lower motoneurons, but the cellular basis for this relative specificity is still unknown. In contrast to nonneuronal cells where the protein is mainly localized in perinuclear regions and the nucleus, Smn is also present in dendrites, axons and axonal growth cones of isolated motoneurons in vitro. However, this distribution has not been shown in vivo and it is not clear whether Smn and hnRNP R are also present in presynaptic axon terminals of motoneurons in postnatal mice. Smn also associates with components not included in the classical SMN complex like RNA-binding proteins FUS, TDP43, HuD and hnRNP R which are involved in RNA processing, subcellular localization and translation. We show here that Smn and hnRNP R are present in presynaptic compartments at neuromuscular endplates of embryonic and postnatal mice. Smn and hnRNP R are localized in close proximity to each other in axons and axon terminals both in vitro and in vivo. We also provide new evidence for a direct interaction of Smn and hnRNP R in vitro and in vivo, particularly in the cytosol of motoneurons. These data point to functions of SMN beyond snRNP assembly which could be crucial for recruitment and transport of RNA particles into axons and axon terminals, a mechanism which may contribute to SMA pathogenesis.}, language = {en} } @article{SendtnerCarrollHoltmannetal.1994, author = {Sendtner, Michael and Carroll, P. and Holtmann, B and Hughes, R. A. and Thoenen, H.}, title = {Ciliary Neurotrophic Factor}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-42545}, year = {1994}, abstract = {No abstract available}, language = {en} } @article{SendtnerStoeckliThoenenetal.1992, author = {Sendtner, Michael and St{\"o}ckli, Kurt A. and Thoenen, Hans and Schmalbruch, H. and Carroll, P. and Kreutzberg, Georg W.}, title = {Ciliary neurotrophic factor prevents the degeneration of motor neurons in mouse mutant progressive motor neuronopathy}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-42563}, year = {1992}, abstract = {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.}, language = {en} } @article{HughesSendtnerGoldfarbetal.1993, author = {Hughes, Richard A. and Sendtner, Michael and Goldfarb, Mitchell and Lindholm, Dan and Thoenen, Hans}, title = {Evidence that fibroblast growth factor 5 is a major muscle-derived survival factor for cultured spinal motoneurons}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-42588}, year = {1993}, abstract = {We examined the potential role of fibroblast growth factor 5 (FGF-5) as a target-derived trophic factor for spinal motoneurons. Northern analysis of total RNA from rat skeletal muscle revealed an FGF-5 mRNA transcript both during the period of embryonic motoneuron death and in the adult. Recombinant human FGF-5 supported the survival of highly enriched cultures of embryonic chick motoneurons. Significant proportions of the motoneuron survival activity of rat skeletal muscle extracts could be immunoprecipitated using an antiserum to FGF-5. The immunoprecipitable activity was present in soluble and matrix-bound forms in embryonic muscle, but bound exclusively to the extracellular matrix in adult muscle. These results, along with the secretory nature of FGF-5, suggest that FGF-5 may act as a target-derived trophic factor for motoneurons.}, language = {en} } @misc{SendtnerArakawaStoecklietal.1991, author = {Sendtner, Michael and Arakawa, Yoshihiro and St{\"o}ckli, Kurt A. and Kreutzberg, Georg W. and Thoenen, Hans}, title = {Effect of ciliary neurotrophic factor (CNTF) on motoneuron survival}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-33048}, year = {1991}, abstract = {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.}, language = {en} } @incollection{ThoenenHughesSendtner1993, author = {Thoenen, Hans and Hughes, Richard A. and Sendtner, Michael}, title = {Towards a comprehensive understanding of the trophic support of motoneurons}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-31117}, publisher = {Universit{\"a}t W{\"u}rzburg}, year = {1993}, abstract = {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.}, language = {en} } @article{SaadatSendtnerRohrer1989, author = {Saadat, S. and Sendtner, Michael and Rohrer, H.}, title = {Ciliary neurotrophic factor induces cholinergic differentiation of rat sympathetic neurons in culture}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-32677}, year = {1989}, abstract = {Ciliary neurotrophic factor (CNTF) influences the levels of choline acetyltransferase (ChAT) and tyrosine hydroxylase (TH) in cultures of dissociated sYmpathetic neurons from newborn rats. In the presence of CNTF both the total and specific activity of ChAT was increased 7 d after culture by 15- and 18-fold, respectively, as compared to cultures kept in the absence of CNTF. Between 3 and 21 d in culture in the presence of CNTF . the total ChAT activity increased by a factor of >100. Immunotitration demonstrated that the elevated ChAT levels were due to an increased number of enzyme molecules. In contrast to the increase in ChAT levels, the total and specific activity levels' of TH were decreased by 42 and 36 \%, respectively, after 7 d in culture. Half-maximal effects for both ChAT increase and TH decrease were obtained at CNTF concentrations of rvO.6 ng and maximal levels were reached at I ng of CNTF per milliliter of medium. The effect of CNTF on TH and ChAT levels were seen in serum-containing medium as well as in serum-free medium. CNTF was shown to have only a small effect on the long-term s.urviVal of rat sympathetic neurons. We therefore concluded that the effects of CNTF on ChAT and TH are not due to selective survival of cells that acquire cholinergic traits in vitro, but are rather due to the induction of cholinergic differentiation of noradrenergic sympathetic neurons.}, language = {en} } @article{SendtnerThoenenHughes1993, author = {Sendtner, Michael and Thoenen, Hans and Hughes, R. A.}, title = {Members of several gene families influence survival of rat motoneurons in vitro and in vivo}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-42652}, year = {1993}, abstract = {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.}, language = {en} } @article{HughesLillienRaffetal.1988, author = {Hughes, Simon M. and Lillien, Laura E. and Raff, Martin C. and Rohrer, Hermann and Sendtner, Michael}, title = {Ciliary neurotrophic factor induces type-2 astrocyte differentiation in culture}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-42660}, year = {1988}, abstract = {We have been studying a population of bipotential glial progenitor cells in the perinatal rat optic nerve and brain in an attempt to understand how cells choose between alternative fates in the developing mammalian central nervous system (CNS). This cell population gives rise initially to oligodendrocytes and then to type-2 astrocytes1 both of which apparently collaborate in sheathing axons in the CNS2,3. In vitro studies suggest that oligodendrocyte differentiation is the constitutive pathway of development for the oligodendrocyte-type-2-astrocyte (O-2A) progenitor cell4,5, whereas type-2 astrocyte differentiation depends on a specific inducing protein6. This protein is present in the developing optic nerve when type-2 astrocytes are differentiating and can induce 0-2A progenitor cells in vitro to express glial fibrillary acidic protein (GFAP)6, a marker of astrocyte differentiation7. Here we show that the type-2-astrocyte-inducing protein is similar or identical to ciliary neutrotrophic factor (CNTF)8,9, which promotes the survival of some types of peripheral neurons in vitro8, including ciliary ganglion neurons8,10. This suggests that CNTF, in addition to its effect on neurons, may be responsible for triggering type-2 astrocyte differentiation in the developing CNS.}, language = {en} } @article{SendtnerThoenenHoltmannetal.1992, author = {Sendtner, Michael and Thoenen, Hans and Holtmann, B. and Kohlbeck, R. and Barde, Y.-A.}, title = {Brain-derived neurotrophic factor prevents the death of motoneurons in newborn rats after nerve section}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-42673}, year = {1992}, abstract = {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.}, language = {en} } @article{SendtnerThoenen1994, author = {Sendtner, Michael and Thoenen, Hans}, title = {Oxidative stress and motorneuron disease}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-42684}, year = {1994}, abstract = {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.}, language = {en} }