Neonatal Death in Mice Lacking Cardiotrophin-like Cytokine is Associated with Multifocal Neuronal Hypoplasia

2008 ◽  
Vol 46 (3) ◽  
pp. 514-519 ◽  
Author(s):  
X. Zou ◽  
B. Bolon ◽  
J. K. Pretorius ◽  
C. Kurahara ◽  
J. McCabe ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Ventral Horn ◽  
Lumbar Spinal Cord ◽  
Facial Nucleus ◽  
In Ovo ◽  
Neuron Survival ◽  
Motor Neuron Survival ◽  
Lumbar Spinal

Mice with null mutations of ciliary neurotrophic factor (Cntf) receptor alpha (Cntf-Rα), or cytokine-like factor 1 (Clf), one component of Cntf-II (a heterodimeric Cntf-Rα ligand), die as neonates from motor neuron loss affecting the facial nucleus and ventral horn of the lumbar spinal cord. Exposure to cardiotrophin-like cytokine (Clc), the other putative Cntf-II element, supports motor neuron survival in vitro and in ovo. Confirmation that Clc ablation induces an equivalent phenotype to Clf deletion would support a role for Clc in the functional Cntf-II complex. In this study, Clc knockout mice had decreased facial motility, did not suckle, died within 24 hours, and had 32% and 29% fewer motor neurons in the facial nucleus and lumbar ventral horn, respectively; thus, Clc is essential for motor neuron survival during development. The concordance of the Clc knockout phenotype with those of mice lacking Cntf-Rα or Clf bolsters the hypothesis that Clc participates in Cntf-II.

scholarly journals Identification of 17 highly expressed genes within mouse lumbar spinal cord anterior horn region from an in-situ hybridization atlas of 3430 genes: implications for motor neuron disease

2014 ◽  
Vol 6 (2) ◽  
Author(s):  
Michael A. Meyer
Keyword(s):  
Spinal Cord ◽  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Motor Neurons ◽  
Ventral Horn ◽  
Janus Kinase ◽  
Anterior Horn ◽  
Lumbar Spinal Cord ◽  
Spinal Motor ◽  
Lumbar Spinal

In an effort to find possible new gene candidates involved in the causation of amyotrophic lateral sclerosis (ALS), a prior version of the on-line brain gene expression atlas GENSAT was extensively searched for selectively intense expression within spinal motor neurons. Using autoradiographic data of <em>in</em>-<em>situ</em> hybridization from 3430 genes, a search for selectively intense activity was made for the anterior horn region of murine lumbar spinal cord sectioned in the axial plane. Of 3430 genes, a group of 17 genes was found to be highly expressed within the anterior horn suggesting localization to its primary cellular constituent, the alpha spinal motor neuron. For some genes, an inter-relationship to ALS was already known, such as for heavy, medium, and light neurofilaments, and peripherin. Other genes identified include: <em>Gamma Synuclein, GDNF, SEMA3A, Extended Synaptotagmin-like protein 1, LYNX1, HSPA12a, Cadherin 22, PRKACA, TPPP3</em> as well as <em>Choline Acetyltransferase, Janus Kinase 1</em>, and the<em> Motor Neuron</em> and <em>Pancreas Homeobox 1</em>. Based on this study, <em>Fibroblast Growth Factor 1</em> was found to have a particularly selective and intense localization pattern to the ventral horn and may be a good target for development of motor neuron disease therapies; further research is needed.

scholarly journals Locomotor Training Increases Synaptic Structure With High NGL-2 Expression After Spinal Cord Hemisection

2019 ◽  
Vol 33 (3) ◽  
pp. 225-231 ◽  
Author(s):  
Kazu Kobayakawa ◽  
Kyleigh Alexis DePetro ◽  
Hui Zhong ◽  
Bau Pham ◽  
Masamitsu Hara ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Motor Neurons ◽  
Ventral Horn ◽  
Lumbar Spinal Cord ◽  
Locomotor Training ◽  
Synaptic Structure ◽  
Cord Injury ◽  
Lumbar Spinal ◽  
Spinal Cord Hemisection ◽  
Activity Dependent

Background. We previously demonstrated that step training leads to reorganization of neuronal networks in the lumbar spinal cord of rodents after a hemisection (HX) injury and step training, including increases excitability of spinally evoked potentials in hindlimb motor neurons. Methods. In this study, we investigated changes in RNA expression and synapse number using RNA-Seq and immunohistochemistry of the lumbar spinal cord 23 days after a mid-thoracic HX in rats with and without post-HX step training. Results. Gene Ontology (GO) term clustering demonstrated that expression levels of 36 synapse-related genes were increased in trained compared with nontrained rats. Many synaptic genes were upregulated in trained rats, but Lrrc4 (coding NGL-2) was the most highly expressed in the lumbar spinal cord caudal to the HX lesion. Trained rats also had a higher number of NGL-2/synaptophysin synaptic puncta in the lumbar ventral horn. Conclusions. Our findings demonstrate clear activity-dependent regulation of synapse-related gene expression post-HX. This effect is consistent with the concept that activity-dependent phenomena can provide a mechanistic drive for epigenetic neuronal group selection in the shaping of the reorganization of synaptic networks to learn the locomotion task being trained after spinal cord injury.

Lasting paraplegia caused by loss of lumbar spinal cord interneurons in rats: no direct correlation with motor neuron loss

2000 ◽  
Vol 93 (2) ◽  
pp. 266-275 ◽  
Author(s):  
Bassam Hadi ◽  
Y. Ping Zhang ◽  
Darlene A. Burke ◽  
Christopher B. Shields ◽  
David S. K. Magnuson
Keyword(s):  
Spinal Cord ◽  
Locomotor Activity ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Lumbar Spinal Cord ◽  
Neuron Loss ◽  
Content Type ◽  
Motor Neuron Loss ◽  
Lumbar Spinal ◽  
Fine Print

Object. The aims of this study were to investigate further the role played by lumbar spinal cord interneurons in the generation of locomotor activity and to develop a model of spinal cord injury suitable for testing neuron replacement strategies. Methods. Adult rats received intraspinal injections of kainic acid (KA). Locomotion was assessed weekly for 4 weeks by using the Basso, Beattie, and Bresnahan (BBB) 21-point locomotor scale, and transcranial magnetic motor evoked potentials (MMEPs) were recorded in gastrocnemius and quadriceps muscles at 1 and 4 weeks. No changes in transcranial MMEP latency were noted following KA injection, indicating that the descending motor pathways responsible for these responses, including the alpha motor neurons, were not compromised. Rats in which KA injections included much of the L-2 segment (10 animals) showed severe locomotor deficits, with a mean BBB score of 4.5 ± 3.6 (± standard deviation). Rats that received lesions rostral to the L-2 segment (four animals) were able to locomote and had a mean BBB score of 14.6 ± 2.6. Three rats that received only one injection bilaterally centered at L-2 (three animals) had a mean BBB score of 3.2 ± 2. Histological examination revealed variable loss of motor neurons limited to the injection site. There was no correlation between motor neuron loss and BBB score. Conclusions. Interneuron loss centered on the L-2 segment induces lasting paraplegia independent of motor neuron loss and white matter damage, supporting earlier suggestions that circuitry critical to the generator of locomotor activity (the central pattern generator) resides in this area. This injury model may prove ideal for studies of neuron replacement strategies.

scholarly journals Mullerian Inhibiting Substance acts as a motor neuron survival factor in vitro

2005 ◽  
Vol 102 (45) ◽  
pp. 16421-16425 ◽  
Author(s):  
P.-Y. Wang ◽  
K. Koishi ◽  
A. B. McGeachie ◽  
M. Kimber ◽  
D. T. MacLaughlin ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Neuron Survival ◽  
Müllerian Inhibiting Substance ◽  
Survival Factor ◽  
Motor Neuron Survival ◽  
Mullerian Inhibiting Substance

scholarly journals Transport and Secretion of the Wnt3 Ligand by Motor Neuron-like Cells and Developing Motor Neurons

Biomolecules ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1898
Author(s):  
Cristina Pinto ◽  
Viviana Pérez ◽  
Jessica Mella ◽  
Miguel Albistur ◽  
Teresa Caprile ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Nerve Terminal ◽  
Motor Nerve ◽  
Motor Nerve Terminal ◽  
In Ovo ◽  
Wnt Ligands ◽  
Postsynaptic Differentiation

The vertebrate neuromuscular junction (NMJ) is formed by a presynaptic motor nerve terminal and a postsynaptic muscle specialization. Cumulative evidence reveals that Wnt ligands secreted by the nerve terminal control crucial steps of NMJ synaptogenesis. For instance, the Wnt3 ligand is expressed by motor neurons at the time of NMJ formation and induces postsynaptic differentiation in recently formed muscle fibers. However, the behavior of presynaptic-derived Wnt ligands at the vertebrate NMJ has not been deeply analyzed. Here, we conducted overexpression experiments to study the expression, distribution, secretion, and function of Wnt3 by transfection of the motor neuron-like NSC-34 cell line and by in ovo electroporation of chick motor neurons. Our findings reveal that Wnt3 is transported along motor axons in vivo following a vesicular-like pattern and reaches the NMJ area. In vitro, we found that endogenous Wnt3 expression increases as the differentiation of NSC-34 cells proceeds. Although NSC-34 cells overexpressing Wnt3 do not modify their morphological differentiation towards a neuronal phenotype, they effectively induce acetylcholine receptor clustering on co-cultured myotubes. These findings support the notion that presynaptic Wnt3 is transported and secreted by motor neurons to induce postsynaptic differentiation in nascent NMJs.

scholarly journals Activation of Divergent Neuronal Cell Death Pathways in Different Target Cell Populations during Neuroadapted Sindbis Virus Infection of Mice

2000 ◽  
Vol 74 (11) ◽  
pp. 5352-5356 ◽  
Author(s):  
Michael B. Havert ◽  
Brian Schofield ◽  
Diane E. Griffin ◽  
David N. Irani
Keyword(s):  
Cell Death ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Sindbis Virus ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Lumbar Spinal Cord ◽  
Cell Death Pathways ◽  
Adult Mice ◽  
Lumbar Spinal

ABSTRACT Infection of adult mice with neuroadapted Sindbis virus (NSV) results in a severe encephalomyelitis accompanied by prominent hindlimb paralysis. We find that the onset of paralysis parallels morphologic changes in motor neuron cell bodies in the lumbar spinal cord and in motor neuron axons in ventral nerve roots, many of which are eventually lost over time. However, unlike NSV-induced neuronal cell death found in the brain of infected animals, the loss of motor neurons does not appear to be apoptotic, as judged by morphologic and biochemical criteria. This may be explained in part by the lack of detectable caspase-3 expression in these cells.

scholarly journals Isolation of Mature Spinal Motor Neurons and Single-cell Analysis Using the Comet Assay of Early Low-level DNA Damage Induced In Vitro and In Vivo

2001 ◽  
Vol 49 (8) ◽  
pp. 957-972 ◽  
Author(s):  
Zhiping Liu ◽  
Lee J. Martin
Keyword(s):  
Dna Damage ◽  
Comet Assay ◽  
Motor Neuron ◽  
Single Cell ◽  
Motor Neurons ◽  
Ventral Horn ◽  
Motor Neuron Degeneration ◽  
Spinal Motor Neurons

We developed an isolation technique for motor neurons from adult rat spinal cord. Spinal cord enlargements were discretely microdissected into ventral horn tissue columns that were trypsin-digested and subjected to differential low-speed centrifugation to fractionate ventral horn cell types. A fraction enriched in α-motor neurons was isolated. Motor neuron enrichment was verified by immunofluorescence for choline acetyltransferase and prelabeling axon projections to skeletal muscle. Adult motor neurons were isolated from naïve rats and were exposed to oxidative agents or were isolated from rats with sciatic nerve lesions (avulsions). We tested the hypothesis, using single-cell gel electrophoresis (comet assay), that hydrogen peroxide, nitric oxide, and peroxynitrite exposure in vitro and axotomy in vivo induce DNA damage in adult motor neurons early during their degeneration. This study contributes three important developments in the study of motor neurons. It demonstrates that mature spinal motor neurons can be isolated and used for in vitro models of motor neuron degeneration. It shows that adult motor neurons can be isolated from in vivo models of motor neuron degeneration and evaluated on a single-cell basis. This study also demonstrates that the comet assay is a feasible method for measuring DNA damage in individual motor neurons. Using these methods, we conclude that motor neurons undergoing oxidative stress from reactive oxygen species and axotomy accumulate DNA damage early in their degeneration. (J Histochem Cytochem 49:957–972, 2001)

scholarly journals The critical role of membralin in postnatal motor neuron survival and disease

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Bo Yang ◽  
Mingliang Qu ◽  
Rengang Wang ◽  
Jon E Chatterton ◽  
Xiao-Bo Liu ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Motor Neurons ◽  
Early Onset ◽  
Critical Role ◽  
Mutant Mice ◽  
Neuron Survival ◽  
Motor Neuron Survival ◽  
Selective Death

Hitherto, membralin has been a protein of unknown function. Here, we show that membralin mutant mice manifest a severe and early-onset motor neuron disease in an autosomal recessive manner, dying by postnatal day 5–6. Selective death of lower motor neurons, including those innervating the limbs, intercostal muscles, and diaphragm, is predominantly responsible for this fatal phenotype. Neural expression of a membralin transgene completely rescues membralin mutant mice. Mechanistically, we show that membralin interacts with Erlin2, an endoplasmic reticulum (ER) membrane protein that is located in lipid rafts and known to be important in ER-associated protein degradation (ERAD). Accordingly, the degradation rate of ERAD substrates is attenuated in cells lacking membralin. Membralin mutations or deficiency in mouse models induces ER stress, rendering neurons more vulnerable to cell death. Our study reveals a critical role of membralin in motor neuron survival and suggests a novel mechanism for early-onset motor neuron disease.

scholarly journals Global transcriptome profile of the developmental principles of in vitro iPSC-to-motor neuron differentiation

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Emilia Solomon ◽  
Katie Davis-Anderson ◽  
Blake Hovde ◽  
Sofiya Micheva-Viteva ◽  
Jennifer Foster Harris ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Acetylcholine Receptors ◽  
Gene Networks ◽  
Spinal Cord Injuries ◽  
Regulatory Gene ◽  
Transcriptome Profile

Abstract Background Human induced pluripotent stem cells (iPSC) have opened new avenues for regenerative medicine. Consequently, iPSC-derived motor neurons have emerged as potentially viable therapies for spinal cord injuries and neurodegenerative disorders including Amyotrophic Lateral Sclerosis. However, direct clinical application of iPSC bears in itself the risk of tumorigenesis and other unforeseeable genetic or epigenetic abnormalities. Results Employing RNA-seq technology, we identified and characterized gene regulatory networks triggered by in vitro chemical reprogramming of iPSC into cells with the molecular features of motor neurons (MNs) whose function in vivo is to innervate effector organs. We present meta-transcriptome signatures of 5 cell types: iPSCs, neural stem cells, motor neuron progenitors, early motor neurons, and mature motor neurons. In strict response to the chemical stimuli, along the MN differentiation axis we observed temporal downregulation of tumor growth factor-β signaling pathway and consistent activation of sonic hedgehog, Wnt/β-catenin, and Notch signaling. Together with gene networks defining neuronal differentiation (neurogenin 2, microtubule-associated protein 2, Pax6, and neuropilin-1), we observed steady accumulation of motor neuron-specific regulatory genes, including Islet-1 and homeobox protein HB9. Interestingly, transcriptome profiling of the differentiation process showed that Ca2+ signaling through cAMP and LPC was downregulated during the conversion of the iPSC to neural stem cells and key regulatory gene activity of the pathway remained inhibited until later stages of motor neuron formation. Pathways shaping the neuronal development and function were well-represented in the early motor neuron cells including, neuroactive ligand-receptor interactions, axon guidance, and the cholinergic synapse formation. A notable hallmark of our in vitro motor neuron maturation in monoculture was the activation of genes encoding G-coupled muscarinic acetylcholine receptors and downregulation of the ionotropic nicotinic acetylcholine receptors expression. We observed the formation of functional neuronal networks as spontaneous oscillations in the extracellular action potentials recorded on multi-electrode array chip after 20 days of differentiation. Conclusions Detailed transcriptome profile of each developmental step from iPSC to motor neuron driven by chemical induction provides the guidelines to novel therapeutic approaches in the re-construction efforts of muscle innervation.

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