scholarly journals Landscape of human spinal cord cell type diversity at midgestation

2021 ◽  
Author(s):  
Jimena Andersen ◽  
Nicholas Thom ◽  
Jennifer L Shadrach ◽  
Xiaoyu Chen ◽  
Neal D Amin ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Motor Neurons ◽  
Motor Behavior ◽  
Cell Types ◽  
Human Spinal Cord ◽  
Early Diversification ◽  
Positional Identity ◽  
Spinal Cord Cell ◽  
Disease Related Genes ◽  
Fetal Stage

Understanding spinal cord generation and assembly is essential to elucidate how motor behavior is controlled and how disorders arise. The cellular landscape of the human spinal cord remains, however, insufficiently explored. Here, we profiled the midgestation human spinal cord with single cell-resolution and discovered, even at this fetal stage, remarkable heterogeneity across and within cell types. Glia displayed diversity related to positional identity along the dorso-ventral and rostro-caudal axes, while astrocytes with specialized transcriptional programs mapped onto distinct histological domains. We discovered a surprisingly early diversification of alpha (α) and gamma (γ) motor neurons that control and modulate contraction of muscle fibers, which was suggestive of accelerated developmental timing in human spinal cord compared to rodents. Together with mapping of disease-related genes, this transcriptional profile of the developing human spinal cord opens new avenues for interrogating the cellular basis of motor control and related disorders in humans.

scholarly journals Single cell transcriptome profiling of the human developing spinal cord reveals a conserved genetic programme with human specific features

2021 ◽  
Author(s):  
Teresa Rayon ◽  
Rory J. Maizels ◽  
Christopher Barrington ◽  
James Briscoe
Keyword(s):  
Gene Expression ◽  
Spinal Cord ◽  
Single Cell ◽  
Motor Neurons ◽  
Neural Tube ◽  
Transcriptome Profiling ◽  
Cell Types ◽  
Human Embryos ◽  
Neuronal Populations ◽  
Cell Transcriptome

AbstractThe spinal cord receives input from peripheral sensory neurons and controls motor output by regulating muscle innervating motor neurons. These functions are carried out by neural circuits comprising molecularly and physiologically distinct neuronal subtypes that are generated in a characteristic spatial-temporal arrangement from progenitors in the embryonic neural tube. The systematic mapping of gene expression in mouse embryos has provided insight into the diversity and complexity of cells in the neural tube. For human embryos, however, less information has been available. To address this, we used single cell mRNA sequencing to profile cervical and thoracic regions in four human embryos of Carnegie Stages (CS) CS12, CS14, CS17 and CS19 from Gestational Weeks (W) 4-7. In total we recovered the transcriptomes of 71,219 cells. Analysis of progenitor and neuronal populations from the neural tube, as well as cells of the peripheral nervous system, in dorsal root ganglia adjacent to the neural tube, identified dozens of distinct cell types and facilitated the reconstruction of the differentiation pathways of specific neuronal subtypes. Comparison with existing mouse datasets revealed the overall similarity of mouse and human neural tube development while highlighting specific features that differed between species. These data provide a catalogue of gene expression and cell type identity in the developing neural tube that will support future studies of sensory and motor control systems and can be explored at https://shiny.crick.ac.uk/scviewer/neuraltube/.

Engrailed-1 and netrin-1 regulate axon pathfinding by association interneurons that project to motor neurons

Development ◽  
1999 ◽  
Vol 126 (19) ◽  
pp. 4201-4212 ◽  
Author(s):  
H. Saueressig ◽  
J. Burrill ◽  
M. Goulding
Keyword(s):  
Spinal Cord ◽  
Motor Neurons ◽  
Molecular Mechanisms ◽  
Axon Growth ◽  
Cell Types ◽  
Second Phase ◽  
Axon Pathfinding ◽  
Cell Type Specific ◽  
Embryonic Spinal Cord ◽  
Ventrolateral Funiculus

During early development, multiple classes of interneurons are generated in the spinal cord including association interneurons that synapse with motor neurons and regulate their activity. Very little is known about the molecular mechanisms that generate these interneuron cell types, nor is it known how axons from association interneurons are guided toward somatic motor neurons. By targeting the axonal reporter gene τ-lacZ to the En1 locus, we show the cell-type-specific transcription factor Engrailed-1 (EN1) defines a population of association neurons that project locally to somatic motor neurons. These EN1 interneurons are born early and their axons pioneer an ipsilateral longitudinal projection in the ventral spinal cord. The EN1 interneurons extend axons in a stereotypic manner, first ventrally, then rostrally for one to two segments where their axons terminate close to motor neurons. We show that the growth of EN1 axons along a ventrolateral pathway toward motor neurons is dependent on netrin-1 signaling. In addition, we demonstrate that En1 regulates pathfinding and fasciculation during the second phase of EN1 axon growth in the ventrolateral funiculus (VLF); however, En1 is not required for the early specification of ventral interneuron cell types in the embryonic spinal cord.

The control of rostrocaudal pattern in the developing spinal cord: specification of motor neuron subtype identity is initiated by signals from paraxial mesoderm

Development ◽  
1998 ◽  
Vol 125 (6) ◽  
pp. 969-982 ◽  
Author(s):  
M. Ensini ◽  
T.N. Tsuchida ◽  
H.G. Belting ◽  
T.M. Jessell
Keyword(s):  
Spinal Cord ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Neural Tube ◽  
Motor Behavior ◽  
Neural Tube Closure ◽  
Paraxial Mesoderm ◽  
Homeodomain Protein ◽  
Mesodermal Cell ◽  
Developing Spinal Cord

The generation of distinct classes of motor neurons is an early step in the control of vertebrate motor behavior. To study the interactions that control the generation of motor neuron subclasses in the developing avian spinal cord we performed in vivo grafting studies in which either the neural tube or flanking mesoderm were displaced between thoracic and brachial levels. The positional identity of neural tube cells and motor neuron subtype identity was assessed by Hox and LIM homeodomain protein expression. Our results show that the rostrocaudal identity of neural cells is plastic at the time of neural tube closure and is sensitive to positionally restricted signals from the paraxial mesoderm. Such paraxial mesodermal signals appear to control the rostrocaudal identity of neural tube cells and the columnar subtype identity of motor neurons. These results suggest that the generation of motor neuron subtypes in the developing spinal cord involves the integration of distinct rostrocaudal and dorsoventral patterning signals that derive, respectively, from paraxial and axial mesodermal cell groups.

Dynamic Computational Model of the Human Spinal Cord Connectome

2019 ◽  
Vol 31 (2) ◽  
pp. 388-416 ◽  
Author(s):  
Jeffrey E. Arle ◽  
Nicolae Iftimia ◽  
Jay L. Shils ◽  
Longzhi Mei ◽  
Kristen W. Carlson
Keyword(s):  
Spinal Cord ◽  
Computational Model ◽  
Cell Types ◽  
Neural Circuitry ◽  
Simulation Software ◽  
Cross Sectional ◽  
Human Spinal Cord ◽  
Starting Point ◽  
The Many ◽  
Future Work

Connectomes abound, but few for the human spinal cord. Using anatomical data in the literature, we constructed a draft connectivity map of the human spinal cord connectome, providing a template for the many calibrations of specialized behavior to be overlaid on it and the basis for an initial computational model. A thorough literature review gleaned cell types, connectivity, and connection strength indications. Where human data were not available, we selected species that have been studied. Cadaveric spinal cord measurements, cross-sectional histology images, and cytoarchitectural data regarding cell size and density served as the starting point for estimating numbers of neurons. Simulations were run using neural circuitry simulation software. The model contains the neural circuitry in all ten Rexed laminae with intralaminar, interlaminar, and intersegmental connections, as well as ascending and descending brain connections and estimated neuron counts for various cell types in every lamina of all 31 segments. We noted the presence of highly interconnected complex networks exhibiting several orders of recurrence. The model was used to perform a detailed study of spinal cord stimulation for analgesia. This model is a starting point for workers to develop and test hypotheses across an array of biomedical applications focused on the spinal cord. Each such model requires additional calibrations to constrain its output to verifiable predictions. Future work will include simulating additional segments and expanding the research uses of the model.

scholarly journals Time-of-Flight Secondary Ion Mass Spectrometry Based Molecular Histology of Human Spinal Cord Tissue and Motor Neurons

2013 ◽  
Vol 85 (18) ◽  
pp. 8741-8748 ◽  
Author(s):  
Jörg Hanrieder ◽  
Per Malmberg ◽  
Olle R. Lindberg ◽  
John S. Fletcher ◽  
Andrew G. Ewing
Keyword(s):  
Mass Spectrometry ◽  
Spinal Cord ◽  
Motor Neurons ◽  
Secondary Ion Mass Spectrometry ◽  
Time Of Flight ◽  
Spinal Cord Tissue ◽  
Human Spinal Cord ◽  
Ion Mass Spectrometry ◽  
Secondary Ion

scholarly journals Regeneration of spinal motor axons: Negative regulation by Celsr2 implicating Cdc42/Rac1 and JNK/c-Jun signaling

2021 ◽  
Author(s):  
Quan Wen ◽  
Huandi Weng ◽  
Tao Liu ◽  
Lingtai Yu ◽  
Tainyun Zhao ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Motor Neurons ◽  
Axon Regeneration ◽  
Neuromuscular Junctions ◽  
Motor Axon ◽  
Neural Repair ◽  
Human Spinal Cord ◽  
Spinal Motor ◽  
Motor Neuron Survival ◽  
Injury Model

AbstractDuring development, cadherins Celsr2 and Celsr3 control axon navigation. Unlike Celsr3, Celsr2 remains expressed in the adult, suggesting unexplored roles in maintenance and repair. Here we show that Celsr2 knockdown promotes motor axon regeneration in mouse and human spinal cord explants and cultured motor neurons. Celsr2 downregulation is accompanied by increased levels of GTP-bound Rac1 and Cdc42, and of JNK and c-Jun proteins. Using a branchial plexus injury model, we show that forelimb functional recovery is improved in Celsr2 mutant versus control mice. Compared to controls, in mutant mice, reinnervated biceps muscles are less atrophic, contain more newly formed neuromuscular junctions, and generate larger electromyographic potentials, while motor neuron survival and axon regeneration are improved. GTP-bound Rac1 and Cdc42, JNK and c-Jun are upregulated in injured mutant versus control spinal cord. In conclusion, Celsr2 negatively regulates motor axon regeneration via Cdc42/Rac1/JNK/c-Jun signaling and is a target for neural repair.

scholarly journals Sex-dependent effects of amyloid precursor-like protein 2 in the SOD1-G37R transgenic mouse model of MND

2021 ◽  
Author(s):  
Phan H. Truong ◽  
Peter J. Crouch ◽  
James B. W. Hilton ◽  
Catriona A. McLean ◽  
Roberto Cappai ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Mouse Model ◽  
Transgenic Mouse ◽  
Motor Neurons ◽  
Neurodegenerative Disorder ◽  
Transgenic Mouse Model ◽  
Muscle Fibres ◽  
Spinal Cord Tissue ◽  
Human Spinal Cord ◽  
End Stage

AbstractMotor neurone disease (MND) is a neurodegenerative disorder characterised by progressive destruction of motor neurons, muscle paralysis and death. The amyloid precursor protein (APP) is highly expressed in the central nervous system and has been shown to modulate disease outcomes in MND. APP is part of a gene family that includes the amyloid precursor-like protein 1 (APLP1) and 2 (APLP2) genes. In the present study, we investigated the role of APLP2 in MND through the examination of human spinal cord tissue and by crossing APLP2 knockout mice with the superoxide dismutase 1 (SOD1-G37R) transgenic mouse model of MND. We found the expression of APLP2 is elevated in the spinal cord from human cases of MND and that this feature of the human disease is reproduced in SOD1-G37R mice at the End-stage of their MND-like phenotype progression. APLP2 deletion in SOD1-G37R mice significantly delayed disease progression and increased the survival of female SOD1-G37R mice. Molecular and biochemical analysis showed female SOD1-G37R:APLP2−/− mice displayed improved innervation of the neuromuscular junction, ameliorated atrophy of muscle fibres with increased APP protein expression levels in the gastrocnemius muscle. These results indicate a sex-dependent role for APLP2 in mutant SOD1-mediated MND and further support the APP family as a potential target for further investigation into the cause and regulation of MND.

scholarly journals FETAL ANATOMY OF THE HUMAN SPINAL CORD

2020 ◽  
Vol 19 (3) ◽  
pp. 5-12
Author(s):  
V. Shkolnikov
Keyword(s):  
Spinal Cord ◽  
White Matter ◽  
Glial Cells ◽  
Motor Neurons ◽  
Gray Matter ◽  
The Body ◽  
Diagnostic Methods ◽  
Large Area ◽  
Intrauterine Development ◽  
Human Spinal Cord

Due to the development and improvement of medical technologies and diagnostic methods, in recent years, the interest of neuromorphologists, neuropathologists, neurosurgeons and reproductive specialists in the histogenesis of the structures of the central nervous system, in particular, the spinal cord, has increased. In the process of macro- and microscopic examination of the spinal cord of human fetuses of 20-21 weeks of intrauterine development, the topography of the thickenings in relation to the parts of the spinal column was established according to our own method, the morphometric parameters of the structures of the spinal cord segments and the regularities of cytoarchitectonics were determined. In 20-21 week old fetuses, the ratio of the length of the spine to the parietococcygeal length of the fetus is 65.0%, and the ratio of the length of the spinal cord to the parietococcygeal length of the fetus is 54.0 %. The border between the cervical and thoracic spine is projected onto a conditional line that connects the spine of the scapula. The border between the thoracic and lumbar regions of the spine is the line between the upper three quarters and the lower one quarter of the body length. The border between the lumbar and sacral parts runs along a conventionally drawn line that connects the posterior lower iliac spines, and the border of the transition of the sacral to the coccygeal is the level of the lower third of the gluteal region. The structure of the gray matter of the spinal cord segments in this age period corresponds to that in people of mature age – the presence of anterior, lateral and posterior horns. A large area of gray matter is observed in the cervical and lumbar segments, a smaller area in the thoracic and sacral segments. The structuredness of the white matter of the spinal cord segments in this age period corresponds to that in adults – the presence of anterior, lateral and posterior cords. The cervical and lumbar segments have a large area of white matter, and in magnitude they are the same. The nuclei of radial glial cells are relatively equal in size in all segments. The thickness of the matrix layer varies throughout the entire spinal cord, but reaches its greatest size in the ventral parts. The sizes of the nuclei of neuroblasts also fluctuate: the nuclei of motor neurons have large sizes, and the smaller ones are inserted and vegetative. The nuclei of glial cells have relatively identical sizes of different segments of the spinal cord, but 2-3 times less than the nuclei of neuroblasts.

scholarly journals 1408. Enterovirus D68 RNA Visualized in the Anterior Horn of the Spinal Cord of a Pediatric Patient with Flaccid Paralysis

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S712-S712
Author(s):  
Matthew R Vogt ◽  
Peter Wright ◽  
William Hickey ◽  
James E Crowe ◽  
Kelli Boyd
Keyword(s):  
Spinal Cord ◽  
Motor Neurons ◽  
The United States ◽  
Surface Proteins ◽  
Anterior Horn ◽  
Human Spinal Cord ◽  
Acute Flaccid Myelitis ◽  
Enterovirus D68 ◽  
Outstanding Question

Abstract Background Acute flaccid myelitis (AFM) is a polio-like paralyzing illness of children. AFM incidence is increasing during every other year outbreaks that occur in the United States simultaneously with outbreaks of enterovirus D68 (EV-D68) infection. Demonstrating that EV-D68 directly causes AFM has been challenging due to rare detection of the virus in the cerebrospinal fluid (CSF) of patients despite frequent detection at nonsterile sites. Murine studies have shown that EV-D68 can infect spinal cord anterior horn motor neurons and cause paralysis, similar to poliovirus. However, a key outstanding question is whether EV-D68 causes AFM in humans by direct viral pathogenesis or by indirect host immunopathogenesis. Methods We investigated the pathogenesis of AFM using tissues from a previously reported case of a 5-year-old boy who presented in fall 2008 with four days of progressive limb and voice weakness followed by incontinence, apnea, and death. He had a CSF pleocytosis of 2094/µL with EV-D68 identified in the CSF by sequencing of the VP1 gene. We designed probes for in situ hybridization (ISH) based on this sequence to stain formalin fixed paraffin embedded tissues from his autopsy. For immunohistochemistry (IHC) we used both commercial polyclonal anti-EV-D68 antibodies and our own human monoclonal antibodies that stain virus infected cells in vitro. Immunophenotyping was done by IHC. Results With ISH we identified EV-D68 RNA in the anterior horn of the patient’s spinal cord, corresponding to the location of motor neuron cell bodies. This area was highly inflamed, with an infiltrate of lymphocytes and macrophages. Viral RNA was in low abundance, and we could not detect viral surface proteins by IHC. Neither RNA nor viral antigen was detected in the lungs, which had extensive inflammatory infiltrate. Conclusion Deaths in AFM patients are rare and often distant from initial presentation, but this patient died four days after onset of weakness, allowing us to directly demonstrate that EV-D68 can infect the human spinal cord. Low abundance of virus suggests the virus either reached the spinal cord prior to weakness onset or was cleared rapidly by the immune response. Therefore, both direct viral pathology and immune factors likely contribute to AFM disease in EV-D68 infection. Disclosures James E. Crowe, Jr, MD, IDBiologics (Board Member, Consultant, Grant/Research Support)Vanderbilt University (Other Financial or Material Support, Inventor on patent related to this abstract)

Sign in / Sign up

Export Citation Format

Share Document