Dedifferentiated Schwann cells secrete progranulin that enhances the survival and axon growth of motor neurons

Glia ◽  
2018 ◽  
Vol 67 (2) ◽  
pp. 360-375 ◽  
Author(s):  
Sujin Hyung ◽  
Sun-Kyoung Im ◽  
Bo Yoon Lee ◽  
Jihye Shin ◽  
Jong-Chul Park ◽  
...  
Keyword(s):  
Schwann Cells ◽  
Motor Neurons ◽  
Axon Growth

scholarly journals Identification of the major proteins that promote neuronal process outgrowth on Schwann cells in vitro.

1988 ◽  
Vol 107 (1) ◽  
pp. 353-361 ◽  
Author(s):  
J L Bixby ◽  
J Lilien ◽  
L F Reichardt
Keyword(s):  
Extracellular Matrix ◽  
Schwann Cells ◽  
Motor Neurons ◽  
Axon Growth ◽  
Strong Candidate ◽  
Peripheral Motor ◽  
Extracellular Matrix Receptors ◽  
Neuronal Growth Cones

Schwann cells have a unique role in regulating the growth of axons during regeneration and presumably during development. Here we show that Schwann cells are the best substrate yet identified for promoting process growth in vitro by peripheral motor neurons. To determine the molecular interactions responsible for Schwann cell regulation of axon growth, we have examined the effects of specific antibodies on process growth in vitro, and have identified three glycoproteins that play major roles. These are the Ca2+-independent cell adhesion molecule (CAM), L1/Ng-CAM; the Ca2+-dependent CAM, N-cadherin; and members of the integrin extracellular matrix receptor superfamily. Two other CAMs present on neurons and/or Schwann cells-N-CAM and myelin-associated glycoprotein-do not appear to be important in regulating process growth. Our results imply that neuronal growth cones use integrin-class extracellular matrix receptors and at least two CAMs--N-cadherin and L1/Ng-CAM-for growth on Schwann cells in vitro and establish each of these glycoproteins as a strong candidate for regulating axon growth and guidance in vivo.

scholarly journals Neuromuscular Development and Disease: Learning From in vitro and in vivo Models

2021 ◽  
Vol 9 ◽  
Author(s):  
Zachary Fralish ◽  
Ethan M. Lotz ◽  
Taylor Chavez ◽  
Alastair Khodabukus ◽  
Nenad Bursac
Keyword(s):  
Skeletal Muscle ◽  
Cell Culture ◽  
Animal Models ◽  
Schwann Cells ◽  
Motor Neurons ◽  
Small Animal ◽  
In Vivo Models ◽  
Small Animal Models

The neuromuscular junction (NMJ) is a specialized cholinergic synaptic interface between a motor neuron and a skeletal muscle fiber that translates presynaptic electrical impulses into motor function. NMJ formation and maintenance require tightly regulated signaling and cellular communication among motor neurons, myogenic cells, and Schwann cells. Neuromuscular diseases (NMDs) can result in loss of NMJ function and motor input leading to paralysis or even death. Although small animal models have been instrumental in advancing our understanding of the NMJ structure and function, the complexities of studying this multi-tissue system in vivo and poor clinical outcomes of candidate therapies developed in small animal models has driven the need for in vitro models of functional human NMJ to complement animal studies. In this review, we discuss prevailing models of NMDs and highlight the current progress and ongoing challenges in developing human iPSC-derived (hiPSC) 3D cell culture models of functional NMJs. We first review in vivo development of motor neurons, skeletal muscle, Schwann cells, and the NMJ alongside current methods for directing the differentiation of relevant cell types from hiPSCs. We further compare the efficacy of modeling NMDs in animals and human cell culture systems in the context of five NMDs: amyotrophic lateral sclerosis, myasthenia gravis, Duchenne muscular dystrophy, myotonic dystrophy, and Pompe disease. Finally, we discuss further work necessary for hiPSC-derived NMJ models to function as effective personalized NMD platforms.

scholarly journals Frizzled3 controls axonal development in distinct populations of cranial and spinal motor neurons

eLife ◽  
2013 ◽  
Vol 2 ◽  
Author(s):  
Zhong L Hua ◽  
Philip M Smallwood ◽  
Jeremy Nathans
Keyword(s):  
Cell Death ◽  
Motor Neurons ◽  
Planar Cell Polarity ◽  
Motor Nerve ◽  
Normal Wave ◽  
Axon Growth ◽  
Axonal Growth ◽  
Cell Complexes ◽  
Developing Neurons

Disruption of the Frizzled3 (Fz3) gene leads to defects in axonal growth in the VIIth and XIIth cranial motor nerves, the phrenic nerve, and the dorsal motor nerve in fore- and hindlimbs. In Fz3−/− limbs, dorsal axons stall at a precise location in the nerve plexus, and, in contrast to the phenotypes of several other axon path-finding mutants, Fz3−/− dorsal axons do not reroute to other trajectories. Affected motor neurons undergo cell death 2 days prior to the normal wave of developmental cell death that coincides with innervation of muscle targets, providing in vivo evidence for the idea that developing neurons with long-range axons are programmed to die unless their axons arrive at intermediate targets on schedule. These experiments implicate planar cell polarity (PCP) signaling in motor axon growth and they highlight the question of how PCP proteins, which form cell–cell complexes in epithelia, function in the dynamic context of axonal growth.

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.

Inhibition of motor axon growth by T-cadherin substrata

Development ◽  
1996 ◽  
Vol 122 (10) ◽  
pp. 3163-3171 ◽  
Author(s):  
B.J. Fredette ◽  
J. Miller ◽  
B. Ranscht
Keyword(s):  
Motor Neurons ◽  
Axon Growth ◽  
Neurite Growth ◽  
Motor Axon ◽  
Spinal Motor Neurons ◽  
Guidance Cue ◽  
Spinal Motor ◽  
Neuron Populations ◽  
Muscle Innervation

As spinal motor neurons project to their hindlimb targets, their growth cones avoid particular regions along their pathway. T-cadherin is discretely distributed in the avoided caudal sclerotome and on extrasynaptic muscle surfaces (B. J. Fredette and B. Ranscht (1994) J. Neurosci. 14, 7331–7346), and therefore, the ability of T-cadherin to inhibit neurite growth was tested in vitro. T-cadherin inhibited neurite extension from select neuron populations both as a substratum, and as a soluble recombinant protein. Anti-T-cadherin antibodies neutralized the inhibition. Spinal motor neurons were inhibited only during the stages of axon growth across the sclerotome and muscle innervation. Inhibitory responses corresponded to neuronal T-cadherin expression, suggesting a homophilic binding mechanism. These results suggest that T-cadherin is a negative guidance cue for motor axon projections.

scholarly journals Transduced Schwann cells promote axon growth and myelination after spinal cord injury

2007 ◽  
Vol 207 (2) ◽  
pp. 203-217 ◽  
Author(s):  
Kevin L. Golden ◽  
Damien D. Pearse ◽  
Bas Blits ◽  
Maneesh S. Garg ◽  
Martin Oudega ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Schwann Cells ◽  
Axon Growth ◽  
Cord Injury

scholarly journals Protocadherin-mediated cell repulsion controls the central topography and efferent projections of the abducens nucleus

2018 ◽  
Author(s):  
Kazuhide Asakawa ◽  
Koichi Kawakami
Keyword(s):  
Motor Neurons ◽  
Axon Growth ◽  
Abducens Nucleus ◽  
Efferent Projection ◽  
Genetic Perturbations ◽  
Soma Size ◽  
Efferent Projections ◽  
Duane Retraction Syndrome ◽  
Motor Nuclei ◽  
Ocular Motor System

SummaryCranial motor nuclei in the brainstem innervate diverse types of head and neck muscles. Failure in establishing these neuromuscular connections causes congenital cranial dysinnervation disorders (CCDDs) characterized by abnormal craniofacial movements. However, mechanisms that link cranial motor nuclei to target muscles are poorly understood at the molecular level. Here, we report that protocadherin-mediated repulsion mediates neuromuscular connection in the ocular motor system in zebrafish. We identify pools of abducens motor neurons that are topographically arranged according to soma size and convergently innervate a single muscle. Disruptions of Duane retraction syndrome-associated transcription factors reveal that these neurons require Mafba/MAFB, but not Sall4/SALL4, for differentiation. Furthermore, genetic perturbations of Pcdh17/Protocadherin-17 result in defective axon growth and soma clumping, thereby abolishing neuromuscular connectivity. Our results suggest that protocadherin-mediated repulsion forms the central topography and efferent projection pattern of the abducens nucleus following Mafba-dependent specification, and imply potential involvement of protocadherins in CCDD etiology.

scholarly journals Failures of nerve regeneration caused by aging or chronic denervation are rescued by restoring Schwann cell c-Jun

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Laura J Wagstaff ◽  
Jose A Gomez-Sanchez ◽  
Shaline V Fazal ◽  
Georg W Otto ◽  
Alastair M Kilpatrick ◽  
...  
Keyword(s):  
Schwann Cell ◽  
Schwann Cells ◽  
Axonal Regeneration ◽  
Nerve Repair ◽  
Axon Growth ◽  
Common Mechanism ◽  
Molecular Pathways ◽  
Chronic Denervation ◽  
Clinical Problems ◽  
Molecular Framework

After nerve injury, myelin and Remak Schwann cells reprogram to repair cells specialized for regeneration. Normally providing strong regenerative support, these cells fail in aging animals, and during chronic denervation that results from slow axon growth. This impairs axonal regeneration and causes significant clinical problems. In mice, we find that repair cells express reduced c-Jun protein as regenerative support provided by these cells declines during aging and chronic denervation. In both cases, genetically restoring Schwann cell c-Jun levels restores regeneration to control levels. We identify potential gene candidates mediating this effect and implicate Shh in the control of Schwann cell c-Jun levels. This establishes that a common mechanism, reduced c-Jun in Schwann cells, regulates success and failure of nerve repair both during aging and chronic denervation. This provides a molecular framework for addressing important clinical problems, suggesting molecular pathways that can be targeted to promote repair in the PNS.

scholarly journals Functional characterization of Neurofilament Light b splicing and misbalance in zebrafish

2020 ◽  
Author(s):  
DL Demy ◽  
ML Campanari ◽  
R Munoz-Ruiz ◽  
HD Durham ◽  
BJ Gentil ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Neuronal Development ◽  
Rna Binding ◽  
De Novo ◽  
Functional Characterization ◽  
Axon Growth ◽  
Motor Deficits ◽  
Neurofilament Light ◽  
Cytoplasmic Inclusions

AbstractNeurofilaments (NFs), a major cytoskeletal component of motor neurons, play a key role in their differentiation, establishment and maintenance of their morphology and mechanical strength. The de novo assembly of these neuronal intermediate filaments requires the presence of the neurofilament light subunit, NEFL, which expression is reduced in motor neurons in Amyotrophic Lateral Sclerosis (ALS). This study used zebrafish as a model to characterize the NEFL homologue neflb, which encodes two different isoforms via splicing of the primary transcript (neflbE4 and neflbE3). In vivo imaging showed that neflb is crucial for proper neuronal development, and that disrupting the balance between its two isoforms specifically affects NF assembly and motor axon growth, with resulting motor deficits. This equilibrium is also disrupted upon partial depletion of TDP-43, a RNA binding protein that is mislocalized into cytoplasmic inclusions in ALS. The study supports interaction of NEFL expression and splicing with TDP-43 in a common pathway, both biologically and pathogenetically.

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