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Biomedical subjects

M Sendtner

Publications and source records attributed to M Sendtner.

At least 19 recordsLinked to original sources
PubMed2005

Effects of root replantation and neurotrophic factor treatment on long-term motoneuron survival and axonal regeneration after C7 spinal root avulsion.

In order to determine the effect of nerve root replantation on motoneuron survival and regeneration, we have avulsed and replanted C7 ventral rootlets in adult rabbits under various conditions. Intraspinal alterations and exact positions of ventrolateral replantations were studied in each animal, and the effects of BDNF and/or CNTF administration during replantation investigated in different experimental groups. Six months after lesion, about 70% of motoneurons were lost on the lesioned sides in the C7 segment, without significant differences between groups. Retrograde fluorescent tracing and histological analysis documented that many axons had regrown through the original ventral exit zones or had exited the spinal cord at the lateral replantation site. However, many laterally exiting axons had not grown out directly from the ventral horn through the lateral white matter but had elongated vertically before leaving the spinal cord. The mean axonal diameter was significantly higher in regenerated axons that had exited through the original ventral exit zones in comparison with axons which had grown out laterally. Application of BDNF and/or CNTF did not show any effects on the pathways of regeneration into the replanted root. The results indicate that motoneuron survival cannot be significantly improved by a single dose of neurotrophic factors applied to a ventrolateral replantation site. However, a significant number of myelinating axons are found in replanted roots, and regeneration may be more efficient when outgrowth through the original ventral exit zone is supported.

Animals↗
PubMed2005

Ciliary neurotrophic factor-immunoreactivity in olfactory sensory neurons.

Ciliary neurotrophic factor (CNTF) has been implicated in processes of neuroprotection, axonal regeneration and synaptogenesis in the lesioned CNS. In the olfactory system, which is characterized by particularly robust neuroplasticity throughout life, the concentration of CNTF is high even under physiological conditions. In the present study, the cellular localization of CNTF-immunoreactivity was studied in the rat and mouse olfactory epithelium. In both species, individual olfactory sensory neurons (ONs) displayed intense CNTF-immunoreactivity. The number of CNTF-ir ONs varied interindividually in rats and was lower in mice than in rats. In olfactory epithelia of mice expressing beta-galactosidase under control of the CNTF promoter, cells of the ON layer were immunoreactive for the reporter protein. CNTF-ir ONs were olfactory marker protein-positive and growth associated protein 43-negative. CNTF-ir ONs lacked apoptotic markers, and the number of specifically labeled ONs was apparently unchanged after light chemical lesioning of the epithelium, indicating that CNTF-immunoreactivity was not associated with ON death. Electron microscopy of CNTF-ir ON axons in innervated olfactory bulb glomeruli documented that they formed typical ON axonal synapses with target neurons. Three dimensional reconstructions of bulb pairs showed a striking similarity of the positions of glomeruli innervated by CNTF-ir ON axons in left and right bulbs of individual animals and interindividually. The number of innervated glomeruli differed interindividually in rats and was lower in mice than in rats. The results show that in rodents CNTF-immunoreactivity occurs in a subset of mature, functionally competent ONs. The localization of target glomeruli suggests that CNTF-immunoreactivity may be associated with the expression and/or activation of specific olfactory receptor proteins.

Animals↗
PubMed2004

Signalling mechanisms for survival of lesioned motoneurons.

Mechanisms controlling neuronal survival play an important role both during development and after birth, in particular when the nervous system is lesioned. Isolated embryonic motoneurons and other types of primary neurons have been a useful tool for studying basic mechanisms underlying neuronal cell death during development and under pathophysiological conditions after neurotrauma. These studies have led to the identification of neurotrophic factors which under physiological conditions regulate survival and functional properties, and after neurotrauma promote regeneration and plasticity. Functional analysis of these molecules, in particular by generation of gene knockout mice, has led to a more detailed understanding of complex requirements of individual types of neurons for their survival and also paved the way for a better understanding of the signalling pathways in lesioned neurons which decide on cell death or survival after axotomy and other pathophysiological conditions. These findings could ultimately lead to a rational basis for therapeutic approaches aiming at improving neuronal survival and regeneration after neurotrauma.

Adenosine Monophosphate↗
PubMed2003

Ciliary neurotrophic factor in the olfactory bulb of rats and mice.

Ciliary neurotrophic factor (CNTF) is primarily regarded as an astrocytic lesion factor, promoting neuronal survival and influencing plasticity processes in deafferented areas of the CNS. Postnatal loss of neurons in CNTF-deficient mice indicates a function of the factor also under physiological conditions. In the olfactory bulb, where neurogenesis, axo- and synaptogenesis continue throughout life, CNTF content is constitutively high. The cellular localization of CNTF in the rat olfactory bulb is not fully resolved, and species differences between mouse and rat are not yet characterized. In the present study, four different CNTF antibodies and double immunolabeling with specific markers for glial and neuronal cells were used to study the cellular localization of CNTF in rat and mouse olfactory bulb. Specificity of the detection was checked with tissue from CNTF-deficient mice, and investigations were complemented by immunolocalization of reporter protein in mice synthesizing beta-galactosidase under control of the CNTF promoter (CNTF lacZ-knock-in mice). In both species, CNTF localized to ensheathing cell nuclei, cell bodies and axon-enveloping processes. Additionally, individual axons of olfactory neurons were CNTF immunoreactive. Both CNTF protein content and immunoreaction intensity were lower in mice than in rats. Scattered lightly CNTF-reactive cells were found in the granular and external plexiform layers in rats. Some CNTF-positive cells were associated with immunoreactivity for the polysialylated form of the neural cell adhesion molecule, which is expressed by maturing interneurons derived from the rostral migratory stream. In CNTF lacZ-knock-in mice, beta-galactosidase reactivity was found in ensheathing cells of the olfactory nerve layer, and in cells of the glomerular, external plexiform and granular layers. The study proves that CNTF is localized in glial and neuronal structures in the rodent olfactory bulb. Results in mice provide a basis for investigations concerning the effects of a lack of the factor in CNTF-deficient mice.

Animals↗
PubMed2001

Neurotrophin receptor-interacting mage homologue is an inducible inhibitor of apoptosis protein-interacting protein that augments cell death.

The inhibitor of apoptosis proteins (IAPs) have been shown to interact with a growing number of intracellular proteins and pathways to fulfil their anti-apoptotic role. In the search for novel IAP-interacting proteins we identified the neurotrophin receptor-interacting MAGE homologue (NRAGE) as being able to bind to the avian IAP homologue ITA. This interaction requires the RING domain of ITA. NRAGE additionally coimmunoprecipitates with XIAP. When overexpressed in 32D cells NRAGE augments interleukin-3 withdrawal induced apoptosis, possibly through binding endogenous XIAP. Moreover, NRAGE is able to overcome the anti-apoptotic effect of Bcl-2.

Animals↗
PubMed2001

Co-regulation of survival of motor neuron (SMN) protein and its interactor SIP1 during development and in spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by the degeneration of motor neurons in the spinal cord. The disease is caused by mutations of the survival of motor neuron 1 gene (SMN1), resulting in a reduced production of functional SMN protein. A major question unanswered thus far is why reduced amounts of ubiquitously expressed SMN protein specifically cause the degeneration of motor neurons without affecting other somatic cell types. In a first attempt to address this issue we have investigated the Smn interacting protein 1 (Sip1), with an emphasis on its developmental expression and subcellular distribution in spinal motor neurons in relation to Smn. By confocal immunofluorescence studies we provide evidence that a significant amount of Smn does not co-localize with Sip1 in neurites of motor neurons, indicating that Smn may exert motor neuron-specific functions that are not dependent on Sip1. Sip1 is highly expressed in the spinal cord during early development and expression decreases in parallel with Smn during postnatal development. Strikingly, reduced production of Smn as observed in cell lines derived from SMA patients or in a mouse model for SMA coincides with a simultaneous reduction of Sip1. The finding that expression of Sip1 and Smn is tightly co-regulated, together with the unique localization of Smn in neurites, may help in understanding the motor neuron-specific defects observed in SMA patients.

Amino Acid Sequence↗
PubMed2001

Cardiotrophin-1, a muscle-derived cytokine, is required for the survival of subpopulations of developing motoneurons.

Developing motoneurons require trophic support from their target, the skeletal muscle. Despite a large number of neurotrophic molecules with survival-promoting activity for isolated embryonic motoneurons, those factors that are required for motoneuron survival during development are still not known. Cytokines of the ciliary neurotrophic factor (CNTF)-leukemia inhibitory factor (LIF) family have been shown to play a role in motoneuron (MN) survival. Importantly, in mice lacking the LIFRbeta or the CNTFRalpha there is a significant loss of MNs during embryonic development. Because genetic deletion of either (or both) CNTF or LIF fails, by contrast, to perturb MN survival before birth, it was concluded that another ligand exists that is functionally inactivated in the receptor deleted mice, resulting in MN loss during development. One possible candidate for this ligand is the CNTF-LIF family member cardiotrophin-1 (CT-1). CT-1 is highly expressed in embryonic skeletal muscle, secreted by myotubes, and promotes the survival of cultured embryonic mouse and rat MNs. Here we show that ct-1 deficiency causes increased motoneuron cell death in spinal cord and brainstem nuclei of mice during a period between embryonic day 14 and the first postnatal week. Interestingly, no further loss was detectable during the subsequent postnatal period, and nerve lesion in young adult ct-1-deficient mice did not result in significant additional loss of motoneurons, as had been previously observed in mice lacking both CNTF and LIF. CT-1 is the first bona fide muscle-derived neurotrophic factor to be identified that is required for the survival of subgroups of developing motoneurons.

Animals↗
PubMed2001

In vivo adenoviral transduction of the neonatal rat cochlea and middle ear.

Virally mediated gene transfer to the adult mammalian ear appears to be a powerful strategy to investigate gene function in the auditory system and to develop new therapeutic treatment for hearing impaired patients. However, there has been little work done in the neonatal middle and inner ear. In this study, a recombinant adenoviral (AdV) vector was used for gene transfer of a beta-galactosidase (beta-gal) reporter gene to the neonatal middle ear and cochlea of 5 day old rats. For transduction of middle ear, AdV was injected through the tympanic membrane into the tympanic cavity. Three and 7 days later, strong expression of beta-gal was observed in epithelial cells of the mucosa, but not in the underlying stroma or mesenchyme. There was little or no infiltration of leukocytes. No expression of beta-gal was detected inside the cochlea or vestibular system. When AdV was injected into the basal turn of the cochlea, high levels of beta-gal expression were observed in cells lining the perilymphatic space and in parts of the spiral ligament 3, 7 and 21 days later. Spiral ganglion cells did not express beta-gal. However, virally mediated gene transfer was observed in some cells of the organ of Corti. A moderate infiltration of leukocytes into the labyrinth was observed, but no vestibular or auditory dysfunction. These results demonstrate that neonatal middle ear and cochlear cells can be successfully transduced with an AdV vector in vivo, without obvious morphological signs of inflammation or cellular damage. AdV vectors provide a tool for investigation of the role of genes in influencing the development of middle and inner ear structures. Virally mediated expression of protective genes could also be used to rescue hair cells or spiral ganglion cells from congenital degeneration or damage.

Adenoviridae↗
PubMed2001

Specific function of B-Raf in mediating survival of embryonic motoneurons and sensory neurons.

Embryonic sensory and motoneurons depend on neurotrophic factors for survival. Here we show that their survival requires B-Raf, which, in this function, cannot be substituted by C-Raf. Sensory and motoneurons from b-raf-deficient mice do not respond to neurotrophic factors for their survival. However, these primary neurons can be rescued by transfection of a b-raf expression plasmid. In contrast, c-raf-deficient neurons survive in response to neurotrophic factors, similarly to neurons from wild-type mice. This points to an essential and specific function of B-Raf in mediating survival of sensory and motoneurons during development.

Animals↗
PubMed2001

Mutations in the gene encoding immunoglobulin mu-binding protein 2 cause spinal muscular atrophy with respiratory distress type 1.

Classic spinal muscular atrophy (SMA) is caused by mutations in the telomeric copy of SMN1. Its product is involved in various cellular processes, including cytoplasmic assembly of spliceosomal small nuclear ribonucleoproteins, pre-mRNA processing and activation of transcription. Spinal muscular atrophy with respiratory distress (SMARD) is clinically and genetically distinct from SMA. Here we demonstrate that SMARD type 1 (SMARD1) results from mutations in the gene encoding immunoglobulin micro-binding protein 2 (IGHMBP2; on chromosome 11q13.2-q13.4). In six SMARD1 families, we detected three recessive missense mutations (exons 5, 11 and 12), two nonsense mutations (exons 2 and 5), one frameshift deletion (exon 5) and one splice donor-site mutation (intron 13). Mutations in mouse Ighmbp2 (ref. 14) have been shown to be responsible for spinal muscular atrophy in the neuromuscular degeneration (nmd) mouse, whose phenotype resembles the SMARD1 phenotype. Like the SMN1 product, IGHMBP2 colocalizes with the RNA-processing machinery in both the cytoplasm and the nucleus. Our results show that IGHMBP2 is the second gene found to be defective in spinal muscular atrophy, and indicate that IGHMBP2 and SMN share common functions important for motor neuron maintenance and integrity in mammals.

Amino Acid Sequence↗
PubMed2001

Molecular mechanisms in spinal muscular atrophy: models and perspectives.

Spinal muscular atrophy is an autosomal-recessive disorder that is caused by homozygous mutations or deletion of the telomeric copy of the survival of motor neurone (SMN) gene on human chromosome 5q13. The SMN gene is present as an inverted repeat in this chromosomal region, and both SMN genes are expressed. They differ by the preferential expression of a full-length transcript from the telomeric copy and a truncated SMN protein from the centromeric SMN gene, which lacks the carboxyl-terminal portions of the protein encoded by exon 7. The SMN protein is part of multiprotein complexes in the cytoplasm and the nucleus that are involved in spliceosomal small-nuclear RNP assembly. This function depends on interaction with spliceosomal Sm core proteins. Recent data have also shown that the SMN protein interacts with RNA polymerase II, thus implying additional functions in messenger RNA transcription, possibly by assembly of RNA polymerase II transcription complexes. Thus, the SMN protein is involved in critical steps of messenger RNA transcription and processing, and current research efforts are directed at identifying the specificity of these defects for the pathophysiological changes in motor neurones that occur in spinal muscular atrophy.

Animals↗
PubMed2001

Motoneuron cell death and neurotrophic factors: basic models for development of new therapeutic strategies in ALS.

Motoneurons are generated in excess during embryonic development of higher vertebrates. In the lumbar spinal cord of the developing rat, about 6000 motoneurons are present at embryonic day 14. These neurons grow out axons which make contact with their target tissue, the skeletal muscle. About 50% of the motoneurons are lost during a critical period from embryonic day 14 until postnatal day 3. This process, which is called physiological motoneuron cell death, has been the focus of research aiming at the identification of neurotrophic factors which regulate motoneuron survival during this developmental period. Motoneuron cell death can also be observed in vitro when the motoneurons are isolated from the embryonic avian or rodent spinal cord. These isolated motoneurons and other types of primary neurons have been a useful tool for studying basic mechanisms underlying neuronal degeneration during development and under pathophysiological conditions in neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS). Accumulating evidence from such studies suggests that some specific requirements of motoneurons for survival and proper function may change during development. These findings might be relevant for understanding the pathophysiological processes underlying ALS and thus could contribute to the development of new therapeutic strategies.

Amyotrophic Lateral Sclerosis↗
PubMed2000

The neuronal apoptosis inhibitory protein suppresses neuronal differentiation and apoptosis in PC12 cells.

The human neuronal apoptosis inhibitory protein (NAIP) gene has been discovered as a candidate gene for spinal muscular atrophy, a genetic disorder characterized by motor neuron loss in the spinal cord. The telomeric NAIP gene on human chromosome 5 is deleted together with survival motor neurons (SMN) in many cases of the most severe forms of the disorder. NAIP, c-IAP1 (inhibitor of apoptosis-1), c-IAP2, X-IAP, survivin and Apollon comprise the mammalian inhibitors of the apoptosis family and contain an N-terminal domain with 1-3 imperfect repeats of an approximately 65 amino acids domain named the baculovirus IAP repeat (BIR) motif. We identified six NAIP genes in the mouse genome which were found to be expressed in a broad range of tissues. Furthermore, we have investigated the effects of NAIP in the rat pheochromocytoma PC12 cell line. These cells differentiate in the presence of nerve growth factor (NGF) into cells that resemble sympathetic neurons. We observed that NAIP overexpression impaired NGF-induced neurite outgrowth. The BIR motifs of NAIP (residues 1-345) were not required for this effect. However, the BIR domains of NAIP were essential to prevent apoptosis in PC12 cells after NGF deprivation or TNF-alpha receptor stimulation. Expression of full-length but not BIR-deleted-NAIP protects against cell death. This correlates with reduced activity of the cell death effector protease, caspase-3, in lysates of NAIP-PC12 cells, as measured by cleavage of the fluorogenic tetrapeptide substrate Asp-Glu-Val-Asp. Thus, unregulation of cellular differentiation and/or caspase suppression may contribute to motoneuron dysfunction and cell death in spinal muscular atrophy where NAIP is mutated.

Amino Acid Motifs↗
PubMed2000

Potential role of LIF as a modifier gene in the pathogenesis of amyotrophic lateral sclerosis.

Leukemia inhibitory factor (lif) is a potent survival factor for motoneurons in cell culture and in vivo. The authors screened 104 patients with ALS and 338 control subjects for mutations in the LIF gene. In four ALS patients, but in no control subject, a G-to-A point mutation at position 3400 was identified, which leads to an amino acid exchange of valine to methionine at position 64 of the mature lif protein. This region of the lif protein (AB loop) interacts with the lif receptor. The authors suggest that LIF could act as a modifier gene which, in combination with other genetic predispositions, might lead to motoneuron disease.

Adult↗
PubMed2000

The human centromeric survival motor neuron gene (SMN2) rescues embryonic lethality in Smn(-/-) mice and results in a mouse with spinal muscular atrophy.

Proximal spinal muscular atrophy (SMA) is a common motor neuron disease in humans and in its most severe form causes death by the age of 2 years. It is caused by defects in the telomeric survival motor neuron gene ( SMN1 ), but patients retain at least one copy of a highly homologous gene, centromeric SMN ( SMN2 ). Mice possess only one survival motor neuron gene ( Smn ) whose loss is embryonic lethal. Therefore, to obtain a mouse model of SMA we created transgenic mice that express human SMN2 and mated these onto the null Smn (-/-)background. We show that Smn (-/-); SMN2 mice carrying one or two copies of the transgene have normal numbers of motor neurons at birth, but vastly reduced numbers by postnatal day 5, and subsequently die. This closely resembles a severe type I SMA phenotype in humans and is the first report of an animal model of the disease. Eight copies of the transgene rescues this phenotype in the mice indicating that phenotypic severity can be modulated by SMN2 copy number. These results show that SMA is caused by insufficient SMN production by the SMN2 gene and that increased expression of the SMN2 gene may provide a strategy for treating SMA patients.

Animals↗
PubMed2000

Reduced survival motor neuron (Smn) gene dose in mice leads to motor neuron degeneration: an animal model for spinal muscular atrophy type III.

Spinal muscular atrophy (SMA) is caused by deletion or specific mutations of the telomeric survival motor neuron ( SMN ) gene on human chromosome 5. The human SMN gene, in contrast to the Smn gene in mouse, is duplicated and the centromeric copy on chromosome 5 codes for transcripts which preferentially lead to C-terminally truncated SMN protein. Here we show that a 46% reduction of Smn protein levels in the spinal cord of Smn heterozygous mice leads to a marked loss of the cytoplasmic Smn pool and motor neuron degeneration resembling spinal muscular atrophy type 3. Smn heterozygous mice described here thus represent a model for the human disease. These mice could allow screening for SMA therapies and help in gaining further understanding of the pathophysiological events leading to motor neuron degeneration in SMA.

Animals↗
PubMed2000

The role of SMN in spinal muscular atrophy.

Childhood spinal muscular atrophy (SMA) is a common autosomal recessive disorder which is characterized by muscle weakness due to degeneration of motoneurons in the spinal cord and brainstem nuclei. Positional cloning strategies have revealed several gene candidates including the genes for the survival motoneuron (SMN) and the neuronal apoptosis inhibitory protein (NAIP). Both genes are duplicated on chromosome 5. Homozygous deletions/mutations of the telomeric SMN gene, which is expressed from both copies on human chromosome 5, are associated with the disease. Recent reports suggest involvement of the SMN protein in the formation of spliceosomal particles in the cytoplasm and in the regeneration of spliceosomes in the nucleus. These data put spinal muscular atrophy into a growing group of disorders of RNA metabolism which also include fragile-X syndrome and myotonic dystrophy. Relevance of these previous data for the pathogenesis of the disease are discussed in this review.

Animals↗