Showing papers on "Motor neuron published in 2002"
TL;DR: It is shown that developmentally relevant signaling factors can induce mouse embryonic stem cells to differentiate into spinal progenitor cells, and subsequently into motor neurons, through a pathway recapitulating that used in vivo.
1,763 citations
TL;DR: Targeted disruption of Olig1 and Olig2 genes sheds light on the ontogeny of oligodendroglia and genetic requirements for their development from multipotent CNS progenitors, indicating that oligod endodendrocytes are derived from Olig-specified progenitor that give rise also to neurons.
1,006 citations
TL;DR: Transgenic overexpression of Cu+2/Zn+2 superoxide dismutase 1 (SOD1) harboring an amyotrophic lateral sclerosis (ALS)-linked familial genetic mutation (S OD1G93A) in a Sprague–Dawley rat results in ALS-like motor neuron disease.
Abstract: Transgenic overexpression of Cu+2/Zn+2 superoxide dismutase 1 (SOD1) harboring an amyotrophic lateral sclerosis (ALS)-linked familial genetic mutation (SOD1G93A) in a Sprague–Dawley rat results in ALS-like motor neuron disease. Motor neuron disease in these rats depended on high levels of mutant SOD1 expression, increasing from 8-fold over endogenous SOD1 in the spinal cord of young presymptomatic rats to 16-fold in end-stage animals. Disease onset in these rats was early, ≈115 days, and disease progression was very rapid thereafter with affected rats reaching end stage on average within 11 days. Pathological abnormalities included vacuoles initially in the lumbar spinal cord and subsequently in more cervical areas, along with inclusion bodies that stained for SOD1, Hsp70, neurofilaments, and ubiquitin. Vacuolization and gliosis were evident before clinical onset of disease and before motor neuron death in the spinal cord and brainstem. Focal loss of the EAAT2 glutamate transporter in the ventral horn of the spinal cord coincided with gliosis, but appeared before motor neuron/axon degeneration. At end-stage disease, gliosis increased and EAAT2 loss in the ventral horn exceeded 90%, suggesting a role for this protein in the events leading to cell death in ALS. These transgenic rats provide a valuable resource to pursue experimentation and therapeutic development, currently difficult or impossible to perform with existing ALS transgenic mice.
852 citations
TL;DR: It is encouraging that the capability of physiological adaptations in the motor pathways remains into very old age — when an appropriate exercise stimulus is given — and long‐term prevention strategies are advocated to avoid excessive physical impairments and activity restrictions in this age group.
Abstract: Loss of cells from the motor system occurs during the normal aging process, leading to reduction in the complement of motor neurons and muscle fibers. The latter age-related decrease in muscle mass has been termed “sarcopenia” and is often combined with the detrimental effects of a sedentary lifestyle in older adults, leading to a significant reduction in reserve capacity of the neuromuscular system, which is the primary subject of this review. Clear evidence of this aging effect is seen when voluntary or stimulated muscle strength is compared across the adult lifespan, with a steady decline of ∼1–2% per year occurring after the sixth decade. Interestingly, when compared with isometric contractions, the effect of aging is more pronounced for concentric movements and less for eccentric movements (i.e., muscle shortening versus lengthening). This phenomenon appears to be linked to the stiffer muscle structures and prolonged myosin crossbridge cycles of aged muscles. It is encouraging that the capability of physiological adaptations in the motor pathways remains into very old age — when an appropriate exercise stimulus is given — and long-term prevention strategies are advocated to avoid excessive physical impairments and activity restrictions in this age group. © 2002 John Wiley & Sons, Inc. Muscle Nerve 25: 17–25, 2002
811 citations
TL;DR: It is suggested that the premotor areas may operate at a hierarchical level comparable to M1 and is proposed that each premotor area is a functionally distinct efferent system that differentially generates and/or controls specific aspects of motor behavior.
602 citations
TL;DR: A mouse model that confirms the critical role of disrupted axonal transport in the pathogenesis of motor neuron degenerative disease is described, and dynamitin overexpression was found to disassemble dynactin, a required activator of cytoplasmic dynein, resulting in an inhibition of retrograde axonal Transport.
552 citations
TL;DR: The actions of transcription factors within motor neuron progenitors, which initiate a cascade of transcriptional interactions that lead to motor neuron specification, are described and the downstream targets of the LIM code are discussed, especially in the context of subtype-specific motor axon pathfinding.
Abstract: The topographic assembly of neural circuits is dependent upon the generation of specific neuronal subtypes, each subtype displaying unique properties that direct the formation of selective connections with appropriate target cells. Studies of motor neuron development in the spinal cord have begun to elucidate the molecular mechanisms involved in controlling motor projections. In this review, we first describe the actions of transcription factors within motor neuron progenitors, which initiate a cascade of transcriptional interactions that lead to motor neuron specification. We next highlight the contribution of the LIM homeodomain (LIM-HD) transcription factors in establishing motor neuron subtype identity. Importantly, it has recently been shown that the combinatorial expression of LIM-HD transcription factors, the LIM code, confers motor neuron subtypes with the ability to select specific axon pathways to reach their distinct muscle targets. Finally, the downstream targets of the LIM code are discussed, especially in the context of subtype-specific motor axon pathfinding.
537 citations
TL;DR: Clinical trials evaluating rHu-EPO's potential to prevent motor neuron apoptosis and the neurological deficits that occur as a consequence of ischemic injury are warranted.
Abstract: The cytokine erythropoietin (EPO) possesses potent neuroprotective activity against a variety of potential brain injuries, including transient ischemia and reperfusion It is currently unknown whether EPO will also ameliorate spinal cord injury Immunocytochemistry performed using human spinal cord sections showed abundant EPO receptor immunoreactivity of capillaries, especially in white matter, and motor neurons within the ventral horn We used a transient global spinal ischemia model in rabbits to test whether exogenous EPO can cross the blood–spinal cord barrier and protect these motor neurons Spinal cord ischemia was produced in rabbits by occlusion of the abdominal aorta for 20 min, followed by saline or recombinant human (rHu)-EPO (350, 800, or 1,000 units/kg of body weight) administered intravenously immediately after the onset of reperfusion The functional neurological status of animals was better for rHu-EPO-treated animals 1 h after recovery from anesthesia, and improved dramatically over the next 48 h In contrast, saline-treated animals exhibited a poorer neurological score at 1 h and did not significantly improve Histopathological examination of the affected spinal cord revealed widespread motor neuron injury associated with positive terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling in control but not in rHu-EPO-treated animals These observations suggest both an acute as well as a delayed beneficial action of rHu-EPO in ischemic spinal cord injury Because rHu-EPO is currently used widely with an excellent safety profile, clinical trials evaluating its potential to prevent motor neuron apoptosis and the neurological deficits that occur as a consequence of ischemic injury are warranted
491 citations
TL;DR: Using in vivo function and protein interaction assays, it is found that Lhx3 binds directly to the LIM cofactor NLI to trigger V2 interneuron differentiation in motor neurons, enabling specific LIM complexes to form in each cell type and ensures that neuronal fates are tightly segregated.
337 citations
TL;DR: Treatment with a selective cyclooxygenase‐2 inhibitor, celecoxib, markedly inhibited production of prostaglandin E2 in the spinal cords of ALS mice, suggesting that cyclo Oxygenase-2 inhibition may benefit ALS patients.
Abstract: The pathogenesis of cell death in amyotrophic lateral sclerosis (ALS) may involve glutamate-mediated excitotoxicity, oxidative damage, and apoptosis. We used a transgenic mouse model of ALS to determine the effect of inhibition of cyclooxygenase-2 in treating the disease. Cyclooxygenase-2, present in spinal neurons and astrocytes, catalyzes the synthesis of prostaglandin E2. Prostaglandin E2 stimulates glutamate release from astrocytes, whereas cyclooxygenase-2 also plays a key role in the production of proinflammatory cytokines, reactive oxygen species, and free radicals. Treatment with a selective cyclooxygenase-2 inhibitor, celecoxib, markedly inhibited production of prostaglandin E2 in the spinal cords of ALS mice. Celecoxib treatment significantly delayed the onset of weakness and weight loss and prolonged survival by 25%. Spinal cords of treated ALS mice showed significant preservation of spinal neurons and diminished astrogliosis and microglial activation. Our results suggest that cyclooxygenase-2 inhibition may benefit ALS patients.
320 citations
TL;DR: Interestingly, hnRNP-R is predominantly located in axons of motor neurons and co-localizes with Smn in this cellular compartment, which could provide a key to understand a motor neuron-specific Smn function in SMA.
Abstract: Spinal muscular atrophy (SMA), the most common hereditary motor neuron disease in children and young adults is caused by mutations in the telomeric survival motor neuron (SMN1) gene. The human genome, in contrast to mouse, contains a second SMN gene (SMN2) which codes for a gene product which is alternatively spliced at the C-terminus, but also gives rise to low levels of full-length SMN protein. The reason why reduced levels of the ubiquitously expressed SMN protein lead to specific motor neuron degeneration without affecting other cell types is still not understood. Using yeast two-hybrid techniques, we identified hnRNP-R and the highly related gry-rbp/hnRNP-Q as novel SMN interaction partners. These proteins have previously been identified in the context of RNA processing, in particular mRNA editing, transport and splicing. hnRNP-R and gry-rbp/hnRNP-Q interact with wild-type Smn but not with truncated or mutant Smn forms identified in SMA. Both proteins are widely expressed and developmentally regulated with expression peaking at E19 in mouse spinal cord. hnRNP-R binds RNA through its RNA recognition motif domains. Interestingly, hnRNP-R is predominantly located in axons of motor neurons and co-localizes with Smn in this cellular compartment. Thus, this finding could provide a key to understand a motor neuron-specific Smn function in SMA.
TL;DR: It is found that oligodendrocytes develop similarly in zebrafish embryos, in that they arise from ventral spinal cord and migrate to new positions and one possibility consistent with these data is that Hedgehog signaling, partly by inducing olig2 expression, specifies neural precursor cells that have potential for primary motor neuron or oligodendedrocyte fate.
TL;DR: Copper-mediated oxidative damage is proposed to play a critical role in the pathogenesis of Cu/Zn superoxide dismutase (SOD1)–linked familial amyotrophic lateral sclerosis (FALS) and CCS is necessary for the efficient incorporation of copper into SOD1 in motor neurons.
Abstract: Mutant SOD1 causes motor neuron disease independent of copper chaperone–mediated copper loading
TL;DR: In this paper, the molecular mechanism underlying motor neuron degeneration in the transgenic mouse model expressing the SOD1 gene with G93A mutation was analyzed using cDNA microarray.
Abstract: Familial amyotrophic lateral sclerosis (FALS)-linked mutations in copper-zinc superoxide dismutase (SOD1) cause motor neuron death through one or more acquired toxic properties. We analyzed the molecular mechanism underlying motor neuron degeneration in the transgenic mouse model expressing the SOD1 gene with G93A mutation. Using cDNA microarray, the differentially expressed genes were identified in the spinal cords of G93A mice, 30 being elevated and seven decreased. cDNA microarray analysis to monitor gene expression during neurodegeneration revealed an up-regulation of genes related to an inflammatory process, such as the tumor necrosis factor-alpha (TNF-alpha) gene, resulting from glial cell activation, together with the change in apoptosis-related gene expression, such as caspase-1. The increased expression of the inflammation- and apoptosis-related genes occurred at 11 weeks of age in the presymptomatic stage prior to motor neuron death. These results suggest a mechanism of neurodegeneration that includes an inflammatory response as an important component. Thus, ALS has paralleled other neurodegenerative disorders, such as Alzheimer's and prion diseases, in which the inflammatory process is believed to participate directly in neuronal death.
TL;DR: The results indicate that the sustained expression of mutant SOD1 leads to proteasomal inhibition and motor neuronal death, which in part explains the pathogenesis of mutantSOD1‐linked ALS.
Abstract: Accumulating evidence indicates that abnormal conformation of mutant superoxide dismutase 1 (SOD1) is an essential feature underlying the pathogenesis of mutant SOD1-linked familial amyotrophic lateral sclerosis (ALS). Here we investigated the role of ubiquitin-proteasome pathway in the mutant SOD1-related cell death and the effect of oxidative stress on the misfolding of mutant SOD1. Transient overexpression of ubiquitin with human SOD1 (wild-type, ala4val, gly85arg, gly93ala) in Neuro2A cells decreased the amount of mutant SOD1, but not of wild-type, while only mutants were co-immunoprecipitated with poly-ubiquitin. Proteasome inhibition by lactacystin augmented accumulation of mutant SOD1 in the non-ionic detergent-insoluble fraction. The spinal cord lysates from mutant SOD1 transgenic mice showed multiple carbonylated proteins, including mutant SOD1 with SDS-resistant dimer formation. Furthermore, the treatment of hSOD1-expressing cells with hydrogen peroxide promoted the oligomerization, and detergent-insolubility of mutant SOD1 alone, and the oxidized mutant SOD1 proteins were more heavily poly-ubiquitinated. In Neuro2A cells stably expressing human SOD1 protein, the proteasome function measured by chymotrypsin-like activity, was decreased over time without a quantitative alteration of the 20S proteasomal component. Finally, primary motor neurons from the mouse embryonic spinal cord were more vulnerable to lactacystin than non-motor neurons. These results indicate that the sustained expression of mutant SOD1 leads to proteasomal inhibition and motor neuronal death, which in part explains the pathogenesis of mutant SOD1-linked ALS.
TL;DR: It is shown that in Pea3 mutant mice, the axons of specific motor neuron pools fail to branch normally within their target muscles, and the cell bodies of these motor neurons are mispositioned within the spinal cord.
TL;DR: In ALS patients and Cu/Zn‐SOD mutant mice, increased oxidative stress occurs in association with the lipid alterations, and exposure of cultured motor neurons to oxidative stress increases the accumulation of sphingomyelin, ceramides, and cholesterol esters.
Abstract: Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of motor neurons in the spinal cord resulting in progressive paralysis and death. The pathogenic mechanism of ALS is unknown but may involve increased oxidative stress, overactivation of glutamate receptors, and apoptosis. We report abnormalities in sphingolipid and cholesterol metabolism in the spinal cords of ALS patients and in a transgenic mouse model (Cu/ZnSOD mutant mice), which manifest increased levels of sphingomyelin, ceramides, and cholesterol esters; in the Cu/ZnSOD mutant mice, these abnormalities precede the clinical phenotype. In ALS patients and Cu/Zn-SOD mutant mice, increased oxidative stress occurs in association with the lipid alterations, and exposure of cultured motor neurons to oxidative stress increases the accumulation of sphingomyelin, ceramides, and cholesterol esters. Pharmacological inhibition of sphingolipid synthesis prevents accumulation of ceramides, sphingomyelin, and cholesterol esters and protects motor neurons against death induced by oxidative and excitotoxic insults. These findings suggest a pivotal role for altered sphingolipid metabolism in the pathogenesis of ALS.
TL;DR: In vivo delivery of human Hsp27 but not a nonphosphorylatable mutant prevents neonatal rat motor neurons from nerve injury-induced death, while knockdown in vitro and in vivo of Hsp 27 in adult injured sensory neurons results in apoptosis.
TL;DR: The use of genetically engineered mouse models that are instrumental for understanding why AD is a neuronal disease, and for validating attractive therapeutic targets, are emphasized.
Abstract: Recent research has significantly advanced our understanding of the molecular mechanisms of neurodegenerative diseases, including Alzheimer's disease (AD) and motor neuron disease. Here we emphasize the use of genetically engineered mouse models that are instrumental for understanding why AD is a neuronal disease, and for validating attractive therapeutic targets. In motor neuron diseases, Cu/Zn superoxide dismutase and survival motor neuron mouse models are useful in testing disease mechanisms and therapeutic strategies for amyotrophic lateral sclerosis (ALS) and spinal motor atrophy, respectively, but the mechanisms that account for selective motor neuron loss remain uncertain. We anticipate that, in the future, therapies based on understanding disease mechanisms will be identified and tested in mouse model systems.
TL;DR: It is suggested that loss of motor neuron cell bodies results from a 'dying-back' axonopathy in SMA, and Smn mutant mice should represent a valuable model for elucidating the pathway linking Smn to cytoskeletal organization.
Abstract: Mutations of survival of the motor neuron gene (SMN1) are responsible for spinal muscular atrophy (SMA), a common genetic cause of death in childhood. The cellular mechanism by which mutations of SMN1 are responsible for the selective neuromuscular defect and motor neuron cell degeneration observed in SMA has not been described. We have previously generated mice carrying a homozygous deletion of Smn exon 7 directed to neurons. We report here that these mutant mice display a dramatic and progressive loss of motor axons involving both proximal and terminal regions, in agreement with the skeletal muscle denervation process and disease progression. Moreover, we found massive accumulation of neurofilaments, including phosphorylated forms, in terminal axons of the remaining neuromuscular junctions. This aberrant cytoskeletal organization of synaptic terminals was associated with reduction of branched structures of the postsynaptic apparatus and defect of axonal sprouting in mutant mice. Together, these findings may be responsible for severe motor neuron dysfunction, and suggest that loss of motor neuron cell bodies results from a 'dying-back' axonopathy in SMA. Smn mutant mice should represent a valuable model for elucidating the pathway linking Smn to cytoskeletal organization.
TL;DR: It is demonstrated that the entry of SOD1 into mitochondria depends on demetallation and that heat shock proteins block the uptake of the FALS-associated mutant S OD1 (G37R, G41D, or G93A), while having no effect on wild-type SOD 1.
Abstract: Missense mutations in Cu,Zn-superoxide dismutase (SOD1) account for ≈20% of familial amyotrophic lateral sclerosis (FALS) through some, as yet undefined, toxic gain of function that leads to gradual death of motor neurons Mitochondrial swelling and vacuolization are early signs of incipient motor neuron death in FALS We previously reported that SOD1 exists in the intermembrane space of mitochondria Herein, we demonstrate that the entry of SOD1 into mitochondria depends on demetallation and that heat shock proteins (Hsp70, Hsp27, or Hsp25) block the uptake of the FALS-associated mutant SOD1 (G37R, G41D, or G93A), while having no effect on wild-type SOD1 The binding of mutant SOD1 to Hsps in the extract of neuroblastoma cells leads to formation of sedimentable aggregates Many antiapoptotic effects of Hsps have been reported We now propose that this binding of Hsps to mutant forms of a protein abundant in motor neurons, such as SOD1, makes Hsps unavailable for their antiapoptotic functions and leads ultimately to motor neuron death It also appears that the Hsp–SOD1 complex recruits other proteins present in the neuroblastoma cell and presumably in motor neurons to form sedimentable aggregates
TL;DR: This work has recorded the discharge of 310 neurons located in the primary motor cortex of two monkeys and discovered discrete groups of functional linkage vectors within the high order muscle space for both monkeys which corresponded to functional properties of the neurons measured by other methods.
Abstract: Many different kinematic and kinetic signals have been proposed as possible variables under the control of the primary motor cortex. Despite the presence of direct projections to motor neurons, muscle activation has received less attention as a controlled variable. Furthermore, although it is well known that descending fibers project to multiple motor pools, an objective, quantitative study of the relation between neuronal modulation and the activity of groups of muscles has not previously been reported. We have recorded the discharge of 310 neurons located in the primary motor cortex of two monkeys, along with the activity of a variety of arm and hand muscles. Data were recorded while the monkey reached to and pressed a series of illuminated buttons. The similarity of a given neuron’s discharge with respect to each muscle was determined by calculating the linear cross-correlation between its discharge rate and each rectified, filtered electromyogram. A “functional linkage vector” was then constructed, which expressed the similarity of that neuron’s discharge to the entire set of muscles. We discovered discrete groups of functional linkage vectors within the high order muscle space for both monkeys which corresponded to functional properties of the neurons measured by other methods. Several of these groups appeared to represent a functional synergy of muscles, such as those required to extend the limb, press a button, or open the hand in preparation for the press. When the dimensionality of this space was reduced by a principal components analysis, the originally identified clusters of neurons remained well separated. These results are consistent with the hypothesis that the discharge of individual neurons in the primary motor cortex encodes the activity of a relatively small number of functionally relevant groups of muscles. It will be important to determine whether these results will also apply to more complex behavior, and to what extent these functional muscle synergy representations remain fixed across behaviors.
TL;DR: This system provides a preclinical screening method for the burgeoning number of drugs postulated for clinical trials in motor neuron disease and a model to evaluate the mechanisms of chronic glutamate toxicity.
Abstract: A dramatic loss of glutamate transport has been observed in sporadic amyotrophic lateral sclerosis and has been postulated to contribute to the disease. Experimentally, this hypothesis was corroborated by mimicking the chronic loss of glutamate transport in post-natal rat spinal cord organotypic cultures through the use of glutamate transport inhibitors. This system is characterized by a relatively selective slow loss of ventral horn motor neurons resulting from glutamate transport inhibition. In this study, spinal cord organotypic cultures were used to test various drugs to evaluate their neuroprotective properties against this slow glutamate-mediated neurotoxicity. The most potent neuroprotectants were drugs that altered glutamate neurotransmission, including non-NMDA receptor antagonists (GYKI-52466, PD144216, and PD139977) and drugs that could block presynaptic release or synthesis (riluzole and gabapentin). In addition, some antioxidants (U83836E and N-t-butyl-α-phenylnitrone) and inhibitors of nitric oxide synthesis (NG-monomethyl-l-arginine acetate) were modestly neuroprotective. The calcium endonuclease inhibitor aurintricarboxylic acid and the calcium release inhibitor dantrolene also provided partial motor neuron protection. However, several antioxidants and calcium channel antagonists had no excitotoxic neuroprotectant activity. This system provides a preclinical screening method for the burgeoning number of drugs postulated for clinical trials in motor neuron disease and a model to evaluate the mechanisms of chronic glutamate toxicity.
TL;DR: GDNF acts as a peripheral signal to induce PEA3 expression in specific motor neuron pools thereby regulating both cell body position and muscle innervation.
TL;DR: The results suggest that SMN may indeed fulfill neuronal- and muscle-specific functions, providing a more plausible mechanism explaining motor neuron degeneration and associated denervation atrophy of skeletal muscles in SMA.
Abstract: Childhood spinal muscular atrophy (SMA) is a common neuromuscular disorder caused by absent or deficient full-length survival motor neuron (SMN) protein. Clinical studies and animal models suggest that SMA is a developmental defect in neuromuscular interaction; however, the role of SMN in this process remains unclear. In the present study, we have determined the subcellular localization of SMN during retinoic-acid-induced neuronal differentiation of mouse embryonal teratocarcinoma P19 cells as well as in skeletal muscle during the critical period of neuromuscular maturation. We demonstrate, for the first time, SMN accumulation in growth-cone- and filopodia-like structures in both neuronal- and glial-like cells, identifying SMN as a new growth cone marker. Indeed, SMN was present at the leading edge of neurite outgrowths, suggesting that SMN may play a role in this process. In addition, SMN was detected as small dot-like particles within the cytoplasm of skeletal muscle during the first 2 weeks after birth, but their number peaked by P6. Intense SMN staining in neuromuscular junctions was observed throughout the entire postnatal period examined. Taken together, these results suggest that SMN may indeed fulfill neuronal- and muscle-specific functions, providing a more plausible mechanism explaining motor neuron degeneration and associated denervation atrophy of skeletal muscles in SMA. The primary SMA pathology most likely initiates in the peripheral axon--the result of deficient neurite outgrowth and/or neuromuscular maturation.
TL;DR: It is reported here that a brief exposure of spinal cord astrocyte monolayers to peroxynitrite provoked long‐lasting reactive morphological changes characterized by process‐bearing cells displaying intense glial fibrillary acidic protein and iNOS immunoreactivity.
Abstract: Oxidative stress mediated by nitric oxide (NO) and its toxic metabolite peroxynitrite has previously been associated with motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Degenerating spinal motor neurons in familial and sporadic ALS are typically surrounded by reactive astrocytes expressing the inducible form of NO synthase (iNOS), suggesting that astroglia may have a pathogenic role in ALS. We report here that a brief exposure of spinal cord astrocyte monolayers to peroxynitrite (0.25-1 mM) provoked long-lasting reactive morphological changes characterized by process-bearing cells displaying intense glial fibrillary acidic protein and iNOS immunoreactivity. Furthermore, peroxynitrite caused astrocytes to promote apoptosis of embryonic motor neurons subsequently plated on the monolayers. Neuronal death occurred within 24 hr after plating, as evidenced by the presence of degenerating motor neurons positively stained for activated caspase-3 and nitrotyrosine. Motor neuron death was largely prevented by NOS inhibitors and peroxynitrite scavengers but not by trophic factors that otherwise will support motor neuron survival in the absence of astrocytes. The bacterial lipopolysaccharide, a well-known inflammatory stimulus that induces iNOS expression in astrocytes, provoked the same effects on astrocytes as peroxynitrite. Thus, spinal cord astrocytes respond to extracellular peroxynitrite by adopting a phenotype that is cytotoxic to motor neurons through peroxynitrite-dependent mechanisms.
TL;DR: Recent data on the neurogenesis, pathfinding, target selection, innervation, and onset of neurotransmitter expression in cholinergic efferent neurons are summarized.
Abstract: Inner ear efferent neurons are part of a descending centrifugal pathway from the hindbrain known across vertebrates as the octavolateralis efferent system. This centrifugal pathway terminates on either sensory hair cells or eighth nerve ganglion cells. Most studies of efferent development have used either avian or mammalian models. Recent studies suggest that prevailing notions of the development of efferent innervation need to be revised. In birds, efferents reside in a single, diffuse nucleus, but segregate according to vestibular or cochlear projections. In mammals, the auditory and vestibular efferents are completely separate. Cochlear efferents can be divided into at least two distinct, descending medial and lateral pathways. During development, inner ear efferents appear to be a specific motor neuron phenotype, but unlike motor neurons have contralateral projections, innervate sensory targets, and, at least in mammals, also express noncholinergic neurotransmitters. Contrary to prevailing views, newer data suggest that medial efferent neurons mature early, are mostly, if not exclusively, cholinergic, and project transiently to the inner hair cell region of the cochlea before making final synapses on outer hair cells. On the other hand, lateral efferent neurons mature later, are neurochemically heterogeneous, and project mostly, but not exclusively to the inner hair cell region. The early efferent innervation to the ear may serve an important role in the maturation of afferent responses. This review summarizes recent data on the neurogenesis, pathfinding, target selection, innervation, and onset of neurotransmitter expression in cholinergic efferent neurons.
TL;DR: This work established an experimental system for the visualization and the quantitative study of retrograde transport in living motor neurons based on a fluorescent fragment of tetanus toxin (TeNT HC), and reveals a novel retrograde route that could be used both by physiological ligands and TeNT to enter the central nervous system.
Abstract: Axonal retrograde transport is essential for neuronal growth and survival. However, the nature and dynamics of the membrane compartments involved in this process are poorly characterized. To shed light on this pathway, we established an experimental system for the visualization and the quantitative study of retrograde transport in living motor neurons based on a fluorescent fragment of tetanus toxin (TeNT HC). Morphological and kinetic analysis of TeNT HC retrograde carriers reveals two major groups of organelles: round vesicles and fast tubular structures. TeNT HC carriers lack markers of the classical endocytic pathway and are not acidified during axonal transport. Importantly, TeNT HC and NGF share the same retrograde transport organelles, which are characterized by the presence of the neurotrophin receptor p75NTR. Our results provide the first direct visualization of retrograde transport in living motor neurons, and reveal a novel retrograde route that could be used both by physiological ligands (i.e., neurotrophins) and TeNT to enter the central nervous system.
TL;DR: Observations indicate that Tbce is critical for the maintenance of microtubules in mouse motor axons, and suggest that altered function of tubulin cofactors might be implicated in human motor neuron diseases.
Abstract: Mice that are homozygous with respect to the progressive motor neuronopathy (pmn) mutation (chromosome 13) develop a progressive caudio-cranial degeneration of their motor axons from the age of two weeks and die four to six weeks after birth1. The mutation is fully penetrant, and expressivity does not depend on the genetic background. Based on its pathological features, the pmn mutation has been considered an excellent model for the autosomal recessive proximal childhood form of spinal muscular atrophy (SMA). Previously, we demonstrated that the genes responsible for these disorders were not orthologous2,3. Here, we identify the pmn mutation as resulting in a Trp524Gly substitution at the last residue of the tubulin-specific chaperone e (Tbce) protein that leads to decreased protein stability. Electron microscopy of the sciatic and phrenic nerves of affected mice showed a reduced number of microtubules, probably due to defective stabilization. Transgenic complementation with a wildtype Tbce cDNA restored a normal phenotype in mutant mice. Our observations indicate that Tbce is critical for the maintenance of microtubules in mouse motor axons, and suggest that altered function of tubulin cofactors might be implicated in human motor neuron diseases.
TL;DR: It is shown that p73 isoforms are essential survival proteins in CNS as well as PNS neurons, and that they likely play a role not only during developmental cell death but also in the long-term maintenance of at least some adult neurons.
Abstract: Here, we show that the p53 family member, p73, is necessary for survival and long-term maintenance of CNS neurons, including postnatal cortical neurons. In p73−/− animals, cortical neuron number is normal at birth but decreases significantly by postnatal day 14 (P14)–P16 because of enhanced apoptosis. This decrease continues into adulthood, when p73−/− animals have approximately one-half as many cortical cells as their wild-type littermates. Cortical neurons express the ΔNp73α protein, and overexpression of ΔNp73 isoforms rescues cortical neurons from diverse apoptotic stimuli. Thus, ΔNp73 isoforms are survival proteins in cortical neurons, and their deletion causes a gradual loss of cortical neurons in the weeks and months after birth. This decrease in CNS neuron number in p73−/− animals is not limited to the cortex; facial motor neuron number is decreased, and postnatal development of the olfactory bulb is greatly perturbed. These findings, together with our previous work showing that ΔNp73 is essential for survival of peripheral sympathetic neurons ([Pozniak et al., 2000][1]), indicate that p73 isoforms are essential survival proteins in CNS as well as PNS neurons, and that they likely play a role not only during developmental cell death but also in the long-term maintenance of at least some adult neurons.
[1]: #ref-31