Showing papers on "Motor neuron published in 2000"
TL;DR: In this article, a mouse model of spinal muscular atrophy (SMA) was obtained using transgenic mice that express human SMN2 and mated these onto the null Smn (-/-)background.
Abstract: 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.
729 citations
TL;DR: It is demonstrated that SMN2 can partially compensate for lack of SMN1, and the variable phenotypes of Smn−/−SMN2 mice reflect those seen in SMA patients, providing a mouse model for this disease.
Abstract: The survival motor neuron gene is present in humans in a telomeric copy, SMN1, and several centromeric copies, SMN2. Homozygous mutation of SMN1 is associated with proximal spinal muscular atrophy (SMA), a severe motor neuron disease characterized by early childhood onset of progressive muscle weakness. To understand the functional role of SMN1 in SMA, we produced mouse lines deficient for mouse Smn and transgenic mouse lines that expressed human SMN2. Smn-/- mice died during the peri-implantation stage. In contrast, transgenic mice harbouring SMN2 in the Smn-/- background showed pathological changes in the spinal cord and skeletal muscles similar to those of SMA patients. The severity of the pathological changes in these mice correlated with the amount of SMN protein that contained the region encoded by exon 7. Our results demonstrate that SMN2 can partially compensate for lack of SMN1. The variable phenotypes of Smn-/-SMN2 mice reflect those seen in SMA patients, providing a mouse model for this disease.
677 citations
TL;DR: In this article, a transgenic line of transgenic zebrafish that expressed green fluorescent protein (GFP) in cranial motor neurons was generated, which enabled visualization of the cell bodies, main axons, and the peripheral branches within the muscles.
Abstract: We generated germ line-transmitting transgenic zebrafish that express green fluorescent protein (GFP) in the cranial motor neurons. This was accomplished by fusing GFP sequences to Islet-1 promoter/enhancer sequences that were sufficient for neural-specific expression. The expression of GFP by the motor neurons in the transgenic fish enabled visualization of the cell bodies, main axons, and the peripheral branches within the muscles. GFP-labeled motor neurons could be followed at high resolution for at least up to day four, when most larval neural circuits become functional, and larvae begin to swim and capture prey. Using this line, we analyzed axonal outgrowth by the cranial motor neurons. Furthermore, by selective application of DiI to specific GFP-positive nerve branches, we showed that the two clusters of trigeminal motor neurons in rhombomeres 2 and 3 innervate different peripheral targets. This finding suggests that the trigeminal motor neurons in the two clusters adopt distinct fates. In future experiments, this transgenic line of zebrafish will allow for a genetic analysis of cranial motor neuron development.
504 citations
TL;DR: Thy1 transgene expression of wild-type human α-synuclein resulted in similar pathological changes, thus supporting a central role for mutant and wild- type α- Synuclein in familial and idiotypic forms of diseases with neuronal α- synucleinopathy and Lewy pathology.
Abstract: The presynaptic protein α-synuclein is a prime suspect for contributing to Lewy pathology and clinical aspects of diseases, including Parkinson's disease, dementia with Lewy bodies, and a Lewy body variant of Alzheimer's disease. α-Synuclein accumulates in Lewy bodies and Lewy neurites, and two missense mutations (A53T and A30P) in the α-synuclein gene are genetically linked to rare familial forms of Parkinson's disease. Under control of mouse Thy1 regulatory sequences, expression of A53T mutant human α-synuclein in the nervous system of transgenic mice generated animals with neuronal α-synucleinopathy, features strikingly similar to those observed in human brains with Lewy pathology, neuronal degeneration, and motor defects, despite a lack of transgene expression in dopaminergic neurons of the substantia nigra pars compacta. Neurons in brainstem and motor neurons appeared particularly vulnerable. Motor neuron pathology included axonal damage and denervation of neuromuscular junctions in several muscles examined, suggesting that α-synuclein interfered with a universal mechanism of synapse maintenance. Thy1 transgene expression of wild-type human α-synuclein resulted in similar pathological changes, thus supporting a central role for mutant and wild-type α-synuclein in familial and idiotypic forms of diseases with neuronal α-synucleinopathy and Lewy pathology. These mouse models provide a means to address fundamental aspects of α-synucleinopathy and test therapeutic strategies.
498 citations
TL;DR: It is speculated that serotonin may influence pattern generation at the cellular level through modulation of plateau properties, an interplay with N-methyl-D-aspartate receptor actions, and afterhyperpolarization regulation.
401 citations
TL;DR: In this paper, the authors describe a bHLH family consisting of three members, two of which (Olig1, Olig2) are expressed in a nervous tissue-specific manner, whereas the third ( Olig3) is found mainly in non-neural tissues.
354 citations
TL;DR: Adding either antioxidants or toxins (FCCP or CN−) that block mitochondrial Ca2+ uptake attenuated AMPA/kainate receptor-mediated motor neuron injury, suggesting that the mitochondrial Ca 2+ uptake and consequent ROS generation are central to the injury process.
Abstract: The reason for the selective vulnerability of motor neurons in amyotrophic lateral sclerosis (ALS) is primarily unknown A possible factor is the expression by motor neurons of Ca(2+)-permeable AMPA/kainate channels, which may permit rapid Ca(2+) influx in response to synaptic receptor activation However, other subpopulations of central neurons, most notably forebrain GABAergic interneurons, consistently express large numbers of these channels but do not degenerate in ALS Indeed, when subjected to identical excitotoxic exposures, motor neurons were more susceptible than GABAergic neurons to AMPA/kainate receptor-mediated neurotoxicity Microfluorimetric studies were performed to examine the basis for the difference in vulnerability First, AMPA or kainate exposures appeared to trigger substantial mitochondrial Ca(2+) loading in motor neurons, as indicated by a sharp increase in intracellular Ca(2+) after addition of the mitochondrial uncoupler carbonyl cyanide p-(trifluoromethoxy)phenyl hydrazone (FCCP) after the agonist exposure The same exposures caused little mitochondrial Ca(2+) accumulation in GABAergic cortical neurons Subsequent experiments examined other measures of mitochondrial function to compare sequelae of AMPA/kainate receptor activation between these populations Brief exposure to either AMPA or kainate caused mitochondrial depolarization, assessed using tetramethylrhodamine ethylester, and reactive oxygen species (ROS) generation, assessed using hydroethidine, in motor neurons However, these effects were only seen in the GABAergic neurons after exposure to the nondesensitizing AMPA receptor agonist kainate Finally, addition of either antioxidants or toxins (FCCP or CN(-)) that block mitochondrial Ca(2+) uptake attenuated AMPA/kainate receptor-mediated motor neuron injury, suggesting that the mitochondrial Ca(2+) uptake and consequent ROS generation are central to the injury process
315 citations
TL;DR: There is a marked decrease in multicatalytic proteasome activity in the spinal cord of Fisher 344 rats at 12, 24 and 28 months, compared with spinal cord tissue from 3-week- and 3-month-old animals, and this data suggest that multic atalytic Proteasome inhibition occurs during aging of the spinal cords, possibly as the result of oxidative stress.
286 citations
TL;DR: The patterns of neurogenesis in mice carrying a targeted mutation in Nkx6.1 show a dorsal-to-ventral switch in the identity of progenitors and in the fate of postmitotic neurons, demonstrating the essential functions of NkX6.
Abstract: There is growing evidence that sonic hedgehog (Shh) signaling regulates ventral neuronal fate in the vertebrate central nervous system through Nkx-class homeodomain proteins. We have examined the patterns of neurogenesis in mice carrying a targeted mutation in Nkx6.1. These mutants show a dorsal-to-ventral switch in the identity of progenitors and in the fate of postmitotic neurons. At many axial levels there is a complete block in the generation of V2 interneurons and motor neurons and a compensatory ventral expansion in the domain of generation of V1 neurons, demonstrating the essential functions of Nkx6.1 in regional patterning and neuronal fate determination.
277 citations
TL;DR: The lack of the nuclear targeting of SMN is identified as the biochemical defect in SMA, and the mutated SMN protein is dramatically reduced in the motor neuron nuclei and causes a lack of gems associated with large aggregates of coilin, a coiled-body-specific protein.
Abstract: Deletion of the murine survival of motor neuron gene (SMN) exon 7, the most frequent mutation found in spinal muscular atrophy (SMA) patients, directed to neurons but not to skeletal muscle, enabled generation of a mouse model of SMA providing evidence that motor neurons are the primary target of the gene defect. Moreover, the mutated SMN protein (SMNDeltaC15) is dramatically reduced in the motor neuron nuclei and causes a lack of gems associated with large aggregates of coilin, a coiled-body-specific protein. These results identify the lack of the nuclear targeting of SMN as the biochemical defect in SMA.
248 citations
TL;DR: More detailed characterisation of the molecular features of human motor neurons in the future may allow the strategic development of better neuroprotective therapies for the benefit of patients afflicted by ALS.
Abstract: Current research evidence suggests that genetic factors, oxidative stress and glutamatergic toxicity, with damage to critical target proteins and organelles, may be important contributory factors to motor neuron injury in amyotrophic lateral sclerosis (ALS). Various molecular and neurochemical features of human motor neurons may render this cell group differentially vulnerable to such insults. Motor neurons are large cells with long axonal processes which lead to requirements for a high level of mitochondrial activity and a high neurofilament content compared to other neuronal groups. The lack of calcium buffering proteins parvalbumin and calbindin D28k and the low expression of the GluR2 AMPA receptor subunit may render human motor neurons particularly vulnerable to calcium toxicity following glutamate receptor activation. Motor neurons also have a high perisomatic expression of the glutamate transporter protein EAAT2 and a very high expression of the cytosolic free radical scavenging enzyme Cu/Zn superoxide dismutase (SOD1) which may render this cell group vulnerable in the face of genetic or post-translational alterations interfering with the function of these proteins. More detailed characterisation of the molecular features of human motor neurons in the future may allow the strategic development of better neuroprotective therapies for the benefit of patients afflicted by ALS.
TL;DR: Double-staining experiments demonstrated that motor neurons clearly expressing GluR2, also expressed Ca(2+)-permeable AMPA receptors, indicating that this subunit is excluded from a subset of AMPA receptor and that the activation of these receptors is responsible for the selective motor neuron death.
TL;DR: It is not clear which of the changes described in the cortex or the motoneurons are responsible for loss of maximal voluntary force and thus contribute to fatigue, and changes may be associated with muscle fatigue without causing it.
Abstract: Fatigue is a reduction of maximal muscle force or power that occurs with exercise. It is accompanied by changes at multiple levels in the motor pathway and also by changes in the discharge patterns of muscle afferents. Changes in afferent firing can lead to altered perceptions and can also act on the efferent pathway. Changes in the motor pathway include slowing of motor unit firing rates during sustained maximal voluntary contractions (MVCs). Muscle responses to stimulation at different levels of the motor pathway also change. Transcranial magnetic stimulation of the motor cortex and stimulation of descending tracts in the spinal cord in human subjects show an increase in the response of the cortex and a decrease in response of the motoneuron pool during sustained MVCs. In addition, the silent period following magnetic stimulation is prolonged. During relaxation after fatiguing exercise, muscle responses to stimulation of the motor cortex are initially facilitated and are then depressed for many minutes, whereas responses to descending tract stimulation are initially depressed but recover over about 2 min. Although some of the loss of force of fatigue does occur through inadequate drive to the muscle, it is not clear which, if any, of the changes described in the cortex or the motoneurons are responsible for loss of maximal voluntary force and thus contribute to fatigue. Changes may be associated with muscle fatigue without causing it.
TL;DR: Genetic evidence is provided that the paired-like homeodomain protein Phox2b is required for the formation of all branchial and visceral, but not somatic, motor neurons in the hindbrain, which exemplifies a novel control point in the generation of CNS neurons.
Abstract: Motor neurons are a widely studied model of vertebrate neurogenesis. They can be subdivided in somatic, branchial and visceral motor neurons. Recent studies on the dorsoventral patterning of the rhombencephalon have implicated the homeobox genes Pax6 and Nkx2.2 in the early divergence of the transcriptional programme of hindbrain somatic and visceral motor neuronal differentiation. We provide genetic evidence that the paired-like homeodomain protein Phox2b is required for the formation of all branchial and visceral, but not somatic, motor neurons in the hindbrain. In mice lacking Phox2b, both the generic and subtype-specific programs of motoneuronal differentiation are disrupted at an early stage. Most motor neuron precursors die inside the neuroepithelium while those that emigrate to the mantle layer fail to switch on early postmitotic markers and to downregulate neuroepithelial markers. Thus, the loss of function of Phox2b in hindbrain motor neurons exemplifies a novel control point in the generation of CNS neurons.
TL;DR: The shift from flaccidity to erection suggests relations among these neuronal populations in response to a variety of informations, and a spinal network consisting of primary afferents from the genitals, spinal interneurons and sympathetic, parasympathetic and somatic nuclei is hypothesize.
TL;DR: It is suggested that sustained or repeated neck flexion may cause ischemic changes in the cervical anterior horn, and application of a cervical collar to minimize neckflexion prevents progressive muscular weakness in an early stage of the disease.
Abstract: This disease is characterized by initially progressive muscular weakness and wasting of the distal upper limb(s) in young people predominantly in men, followed by a spontaneous arrest within several years. This disease has been thought to be separate from motor neuron diseases, yet some authors still consider the illness a variant of motor neuron disease. However, the pathological evidence of ischemic changes in the lower cervical anterior horn should facilitate differentiation of the disorder from degenerative motor neuron disease. Recent radiological investigations proved compressive flattening of the lower cervical cord due to forward displacement of the cervical dural sac and spinal cord induced by neck flexion. These findings suggest that sustained or repeated neck flexion may cause ischemic changes in the cervical anterior horn. Application of a cervical collar to minimize neck flexion prevents progressive muscular weakness in an early stage of the disease.
TL;DR: It is shown that a 46% reduction in 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.
Abstract: 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.
TL;DR: It is shown that even without spike activity, the neonatal rat spinal cord could produce a stable motor rhythm mediated by the synchronization of motor neuron oscillations across gap junctions, which suggests that neural coordination across gapjunctions is important in motor-pattern generation in the mammalian spinal cord.
Abstract: Coordination of neuronal activity to produce movement is generally thought to depend on spike activity in premotor interneuronal networks Here we show that even without such activity, the neonatal rat spinal cord could produce a stable motor rhythm mediated by the synchronization of motor neuron oscillations across gap junctions These rhythms, however, were not coordinated between motor pools in different parts of the spinal cord We further showed that neural coordination through gap junctions contributed to the fundamental organization and function of spinal motor systems These results suggest that neural coordination across gap junctions is important in motor-pattern generation in the mammalian spinal cord
TL;DR: This paper showed that the stoichiometry of cytoskeletal protein expression in ALS spinal motor neurons is significantly altered in a pattern conducive to the formation of neurofilamentous aggregates.
Abstract: Because transgenic mice expressing an altered stoichiometry of neurofilament proteins develop a motor neuron degeneration associated with neurofilamentous aggregate formation similar to that found in amyotrophic lateral sclerosis (ALS), we studied the expression of intermediate filament proteins in sporadic ALS. Archival cervical spinal cord paraffin-embedded sections from 11 disease and 11 control cases were studied by either in situ hybridization using 35S-labeled riboprobes or immunohistochemically using specific antibodies for the individual neurofilament subunit proteins, α-internexin, nestin, peripherin, vimentin, β-actin, or Tα1-tubulin. Median NFL, α-internexin, and peripherin steady-state mRNA levels were significantly reduced in the lateral motor neuron cell column (p < 0.05) of ALS cases, while neither NFM nor NFH mRNA levels were altered. ALS cases demonstrated an elevation of β-actin mRNA levels (p < 0.01) with no increase in Tα1-tubulin mRNA levels. No motor neuronal expression of nestin or vimentin was observed. Ubiquitin-immunoreactive perikaryal aggregates were immunoreactive for NFH or β-actin, but not for peripherin, α-internexin, vimentin, or nestin. In contrast, neuroaxonal spheroids were strongly immunoreactive for NFH and peripherin, but not for β-actin, α-internexin, vimentin, or nestin. These findings suggest that the stoichiometry of cytoskeletal protein expression in ALS spinal motor neurons is significantly altered in a pattern conducive to the formation of neurofilamentous aggregates.
TL;DR: The 88.3% rate of detection of enterovirus nucleic acids in the neuronal cell bodies within the gray matter of the spinal cord of patients with ALS strongly suggests association between persistent EV RNA and ALS.
Abstract: Objective: To investigate the possible association of persistent enterovirus (EV) infection with the development of ALS. Background: Although ALS is a clinically well-defined motor neuron disease, little is known about the etiology and pathogenesis of the sporadic cases. Among the different causes that have been hypothesized, conflicting results have been reported about the possible role of persistent enteroviral infection. Methods: Reverse transcriptase-PCR (RT-PCR) and direct RT in situ PCR (RT-IS-PCR) were performed in formaldehyde-fixed spinal cord samples of 17 patients with confirmed ALS and 29 control subjects with no history of motor neuron disease. When obtained, PCR products were sequenced subsequently. Results: Using direct RT-IS-PCR, EV nucleic acid sequences were detected in 15 (88.3%) of 17 patients with ALS compared to 1 (3.4%) of 29 control subjects. PCR products were located in neuronal cell bodies of the anterior horns of the spinal cord. The RT-PCR products obtained in 13 of the 17 patients with ALS showed between 94% and 86% homology with echovirus 7 sequences. Conclusion: The 88.3% rate of detection of enterovirus (EV) nucleic acids in the neuronal cell bodies within the gray matter of the spinal cord of patients with ALS strongly suggests association between persistent EV RNA and ALS. Further work is required to confirm that the persisting EV sequences we detected are somehow involved in the development of ALS.
TL;DR: The present findings suggest that SMN protein may be transported via axoplasmic flow in maturing neurons, and could play a role in the motoneuronal degeneration and impaired axonal sprouting observed in spinal muscular atrophy.
Abstract: The subcellular localization of the survival motor neuron (SMN) protein, encoded by the spinal muscular atrophy determining gene, was investigated in motor neurons of the developing and adult rat spinal cord by light and electron microscopy immunocytochemistry. The experiments were carried out with a panel of anti-SMN antibodies, all recognizing an SMN-specific protein band at 39 kDa in HeLa cells and rat spinal cord protein extracts. SMN protein expression decreased during postnatal spinal cord development, but it remained unchanged in distribution and intensity in motor neurons at all ages examined. SMN protein was mainly organized in immunoreactive aggregates sparse in the nucleoplasm and cytoplasm of both mature and developing motor neurons, and it was more rarely localized within the endoplasmic reticulum and in apposition to the external mitochondrial membrane. Most strikingly, the SMN protein was found in association with cytoskeletal elements in spinal dendrites and axons, where it was particularly evident during postnatal development. The present findings suggest that SMN protein may be transported via axoplasmic flow in maturing neurons. Given the RNA-binding activity of SMN, the SMN protein could be involved in the transport of specific mRNAs in axons and dendrites of motor neurons. The reduced transport of specific mRNAs within motor neurons during development could play a role in the motoneuronal degeneration and impaired axonal sprouting observed in spinal muscular atrophy.
TL;DR: Recent data showing that the neonatal rat spinal cord can produce a stable motor rhythm in the absence of spike activity in premotor interneuronal networks is discussed, showing the functional relevance for such coordinated oscillations in immature and mature spinal motor systems.
TL;DR: The spontaneous embryonic and neonatal network-driven activity, detected at the levels of motoneurons and primary afferent terminals, may play a role in neuronal maturation and in the formation and refinement of sensorimotor connections.
TL;DR: The first successful transduction and protection of spinal motoneurons by direct gene transfer in a model of progressive motoneuron disease is described, which supports the use of AAVs for the delivery of protective genes to spinal cord moto-neurons as a possible way to enhance mot oneuron survival and repair.
Abstract: Mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) underlie some familial cases of amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder characterized by loss of cortical, brainstem and spinal motoneurons. Transgenic mice over- expressing a mutated form of human SOD1 containing a Gly-->Ala substitution at position 93 (SOD1(G93A)) develop a severe, progressive motoneuron disease. We investigated the potential of recombinant adeno-associated virus (rAAV) to transfer neuroprotective molecules in this animal ALS model. Initial experiments showed that injection of an rAAV vector encoding green fluorescent protein unilaterally into the lumbar spinal cord of wild-type mice leads to expression of the reporter gene in 34.7 +/- 5.2% of the motoneurons surrounding the injection site. Intraspinal injection of an rAAV encoding the anti-apoptotic protein bcl-2 in SOD1 (G93A) mice resulted in sustained bcl-2 expression in motoneurons and significantly increased the number of surviving motoneurons at the end-stage of disease. Moreover, the compound muscle action potential amplitude elicited by nerve stimulation and recorded by electromyographic measurements was higher in the rAAV-bcl-2-treated group than in controls. Local bcl-2 expression in spinal motoneurons delayed the appearance of signs of motor deficiency but was not sufficient to prolong the survival of SOD1 (G93A) mice. To our know-ledge, this study describes the first successful transduction and protection of spinal motoneurons by direct gene transfer in a model of progressive motoneuron disease. Our results support the use of AAVs for the delivery of protective genes to spinal cord moto-neurons as a possible way to enhance motoneuron survival and repair.
TL;DR: Re-examination has revealed ubiquitin-positive but tau-negative inclusions as well as neurites in the frontotemporal cortices and ubiquit inclusions in the granule cells of the dentate fascia, but none were seen in brainstem or spinal cord motor neurons.
Abstract: Three cases are reported with dementia and ubiquitin-positive but tau-negative inclusion bodies. All patients had a semantic dementia and the clinical details of two of these have been published as the first description of a selective semantic memory impairment. The original diagnosis had been of Pick's disease based on frontotemporal atrophy, but re-examination has revealed ubiquitin-positive but tau-negative inclusions as well as neurites in the frontotemporal cortices and ubiquitin-positive, intracytoplasmic inclusions in the granule cells of the dentate fascia. These inclusions are identical to those reported in association with amyotrophic lateral sclerosis (motor neuron disease), but none were seen in brainstem or spinal cord motor neurons.
TL;DR: To investigate the nonspecific versus genetically controlled regulation of motor connectivity, all motor neurons were forced to express ectopically a LIM gene combination appropriate for the subgroup that innervates axial muscles, and it is shown that this genetic alteration is sufficient to convert the cell body settling pattern, gene-expression profile and axonal projections of all motor neuron to that of the axial subclass.
Abstract: Many lines of evidence indicate that genetically distinct subtypes of motor neurons are specified during development, with each type having characteristic properties of axon guidance and cell-body migration. Motor neuron subtypes express unique combinations of LIM-type homeodomain factors that may act as intrinsic genetic regulators of the cytoskeletal events that mediate cell migration, axon navigation or both. Although experimentally displaced motor neurons can pioneer new routes to their targets, in many cases the axons of motor neurons in complete isolation from their normal territories passively follow stereotypical pathways dictated by the environment. To investigate the nonspecific versus genetically controlled regulation of motor connectivity we forced all motor neurons to express ectopically a LIM gene combination appropriate for the subgroup that innervates axial muscles. Here we show that this genetic alteration is sufficient to convert the cell body settling pattern, gene-expression profile and axonal projections of all motor neurons to that of the axial subclass. Nevertheless, elevated occupancy of the axial pathway can override their genetic program, causing some axons to project to alternative targets.
TL;DR: Observations suggest that NP-NF immunoreactivity is a good marker for motor neurons in health and disease and may be a useful tool for studies of motor neuron degeneration (MND).
TL;DR: It is concluded that p53 may participate in the mechanisms for motor neuron apoptosis in ALS.
TL;DR: The data suggest that cnd-1 may specify the identity of ventral cord motor neurons both by maintaining the mitotic competence of their precursors and by modulating the expression of neuronal type-specific determination factors.
Abstract: The basic helix-loop-helix transcription factor NeuroD (Neurod1) has been implicated in neuronal fate determination, differentiation and survival. Here we report the expression and functional analysis of cnd-1, a C. elegans NeuroD homolog. cnd-1 expression was first detected in neuroblasts of the AB lineage in 14 cell embryos and maintained in many neuronal descendants of the AB lineage during embryogenesis, diminishing in most terminally differentiated neurons prior to hatching. Specifically, cnd-1 reporter genes were expressed in the precursors of the embryonic ventral cord motor neurons and their progeny. A loss-of-function mutant, cnd-1(ju29), exhibited multiple defects in the ventral cord motor neurons. First, the number of motor neurons was reduced, possibly caused by the premature withdrawal of the precursors from mitotic cycles. Second, the strict correlation between the fate of a motor neuron with respect to its lineage and position in the ventral cord was disrupted, as manifested by the variable expression pattern of motor neuron fate specific markers. Third, motor neurons also exhibited defects in terminal differentiation characteristics including axonal morphology and synaptic connectivity. Finally, the expression patterns of three neuronal type-specific transcription factors, unc-3, unc-4 and unc-30, were altered. Our data suggest that cnd-1 may specify the identity of ventral cord motor neurons both by maintaining the mitotic competence of their precursors and by modulating the expression of neuronal type-specific determination factors. cnd-1 appears to have combined the functions of several vertebrate neurogenic bHLH proteins and may represent an ancestral form of this protein family.
TL;DR: It is concluded that NaCh6 is widely distributed in the central and peripheral nervous systems and is likely to be important for the electrical properties of the axon and dendrite.
Abstract: Sodium channel 6 (NaCh6) is the α-subunit of a voltage-gated sodium channel expressed in the rat nervous system. The mRNA for this isoform has been shown to be expressed in both neuronal and glial cells by in situ hybridization. To examine localization of NaCh6 protein, polyclonal antibodies specific for NaCh6 were generated against peptides from two cytoplasmic domains and a fusion protein from an extracellular domain. Affinity-purified antibodies were used to localize NaCh6 in the brain, spinal cord, peripheral nervous system, and neuromuscular junction. There was widespread labeling of neurons in the brain and spinal cord. NaCh6 was present in both sensory and motor pathways. Radial glial cells in the cerebellum were intensely labeled for both GFAP and NaCh6. At the subcellular level, NaCh6 is found in axons, dendrites, and the cell body. Motor neurons and primary sensory neurons in dorsal root ganglia had strong cytoplasmic and axonal staining. Nodes of Ranvier in peripheral nerve and in the spinal cord were also intensely labeled. Motor neuron axons near the neuromuscular junction were labeled up to, but not including, terminal boutons. Dendrites of pyramidal cells in the cortex, hippocampus, and cerebellum were labeled. NaCh6 is the first NaCh subtype to be localized either at the node of Ranvier or to a dendrite. We conclude that NaCh6 is widely distributed in the central and peripheral nervous systems and is likely to be important for the electrical properties of the axon and dendrite. J. Comp. Neurol. 420:70–83, 2000. © 2000 Wiley-Liss, Inc.