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Nature Neuroscience Apr 2016Directing the differentiation of induced pluripotent stem cells into motor neurons has allowed investigators to develop new models of amyotrophic lateral sclerosis... (Review)
Review
Directing the differentiation of induced pluripotent stem cells into motor neurons has allowed investigators to develop new models of amyotrophic lateral sclerosis (ALS). However, techniques vary between laboratories and the cells do not appear to mature into fully functional adult motor neurons. Here we discuss common developmental principles of both lower and upper motor neuron development that have led to specific derivation techniques. We then suggest how these motor neurons may be matured further either through direct expression or administration of specific factors or coculture approaches with other tissues. Ultimately, through a greater understanding of motor neuron biology, it will be possible to establish more reliable models of ALS. These in turn will have a greater chance of validating new drugs that may be effective for the disease.
Topics: Amyotrophic Lateral Sclerosis; Animals; Cell Differentiation; Cells, Cultured; Coculture Techniques; Humans; Induced Pluripotent Stem Cells; Motor Neurons
PubMed: 27021939
DOI: 10.1038/nn.4273 -
Brain Research Bulletin Jun 2020Amyotrophic Lateral Sclerosis (ALS) is a progressive, neurodegenerative disease characterized by loss of upper motor neurons (UMN) and lower motor neurons (LMN). Disease... (Review)
Review
Amyotrophic Lateral Sclerosis (ALS) is a progressive, neurodegenerative disease characterized by loss of upper motor neurons (UMN) and lower motor neurons (LMN). Disease affects people all over the world and is more prevalent in men. Patients with ALS develop extensive muscle wasting, paralysis and ultimately death, with a median survival of usually fewer than five years after disease onset. ALS may be sporadic (sALS, 90%) or familial (fALS, 10%). The large majority of fALS cases are associated with genetic alterations, which are mainly related to the genes SOD1, TDP-43, FUS, and C9ORF72. In vitro and in vivo models have helped elucidate ALS etiology and pathogenesis, as well as its molecular, cellular, and physiological mechanisms. Many studies in cell cultures and animal models, such as Caenorhabditis elegans, Drosophila melanogaster, zebrafish, rodents, and non-human primates have been performed to clarify the relationship of these genes to ALS disease. However, there are inherent limitations to consider when using experimental models. In this review, we provide an updated overview of the most used in vitro and in vivo studies that have contributed to a better understanding of the different ALS pathogenic mechanisms.
Topics: Amyotrophic Lateral Sclerosis; Animals; Disease Models, Animal; Humans; Motor Neurons; Superoxide Dismutase-1
PubMed: 32247802
DOI: 10.1016/j.brainresbull.2020.03.012 -
Stem Cell Research Oct 2018Primary rodent neurons and immortalised cell lines have overwhelmingly been used for in vitro studies of traumatic injury to peripheral and central neurons, but have...
Primary rodent neurons and immortalised cell lines have overwhelmingly been used for in vitro studies of traumatic injury to peripheral and central neurons, but have some limitations of physiological accuracy. Motor neurons (MN) derived from human induced pluripotent stem cells (iPSCs) enable the generation of cell models with features relevant to human physiology. To facilitate this, it is desirable that MN protocols both rapidly and efficiently differentiate human iPSCs into electrophysiologically active MNs. In this study, we present a simple, rapid protocol for differentiation of human iPSCs into functional spinal (lower) MNs, involving only adherent culture and use of small molecules for directed differentiation, with the ultimate aim of rapid production of electrophysiologically functional cells for short-term neural injury experiments. We show successful differentiation in two unrelated iPSC lines, by quantifying neural-specific marker expression, and by evaluating cell functionality at different maturation stages by calcium imaging and patch clamping. Differentiated neurons were shown to be electrophysiologically altered by uniaxial mechanical deformation. Spontaneous network activity decreased with applied stretch, indicating aberrant network connectivity. These results demonstrate the feasibility of this rapid, simple protocol for differentiating iPSC-derived MNs, suitable for in vitro neural injury studies focussing on electrophysiological alterations caused by mechanical deformation or trauma.
Topics: Cell Differentiation; Cells, Cultured; Electrophysiology; Humans; Induced Pluripotent Stem Cells; Motor Neurons
PubMed: 30278374
DOI: 10.1016/j.scr.2018.09.006 -
Nature Neuroscience Apr 2021The spinal cord is a fascinating structure that is responsible for coordinating movement in vertebrates. Spinal motor neurons control muscle activity by transmitting...
The spinal cord is a fascinating structure that is responsible for coordinating movement in vertebrates. Spinal motor neurons control muscle activity by transmitting signals from the spinal cord to diverse peripheral targets. In this study, we profiled 43,890 single-nucleus transcriptomes from the adult mouse spinal cord using fluorescence-activated nuclei sorting to enrich for motor neuron nuclei. We identified 16 sympathetic motor neuron clusters, which are distinguishable by spatial localization and expression of neuromodulatory signaling genes. We found surprising skeletal motor neuron heterogeneity in the adult spinal cord, including transcriptional differences that correlate with electrophysiologically and spatially distinct motor pools. We also provide evidence for a novel transcriptional subpopulation of skeletal motor neuron (γ*). Collectively, these data provide a single-cell transcriptional atlas ( http://spinalcordatlas.org ) for investigating the organizing molecular logic of adult motor neuron diversity, as well as the cellular and molecular basis of motor neuron function in health and disease.
Topics: Animals; Autonomic Nervous System; Mice; Motor Neurons; Muscle, Skeletal; Single-Cell Analysis; Spinal Cord; Transcriptome; Viscera
PubMed: 33589834
DOI: 10.1038/s41593-020-00795-0 -
Brain : a Journal of Neurology Nov 2022Penfield’s motor homunculus anthropomorphizes the cerebral level of motor control, the upper motor neuron. However, it leaves the cranial and spinal motor neurons...
Penfield’s motor homunculus anthropomorphizes the cerebral level of motor control, the upper motor neuron. However, it leaves the cranial and spinal motor neurons unrepresented. Here Ravits and Stack redress the imbalance by presenting a lower motor neuron homunculus.
Topics: Female; Humans; Motor Neurons; Teratoma; Ovarian Neoplasms
PubMed: 36029046
DOI: 10.1093/brain/awac310 -
Neuron Dec 2022How the vascular and neural compartment cooperate to achieve such a complex and highly specialized structure as the central nervous system is still unclear. Here, we...
How the vascular and neural compartment cooperate to achieve such a complex and highly specialized structure as the central nervous system is still unclear. Here, we reveal a crosstalk between motor neurons (MNs) and endothelial cells (ECs), necessary for the coordinated development of MNs. By analyzing cell-to-cell interaction profiles of the mouse developing spinal cord, we uncovered semaphorin 3C (Sema3C) and PlexinD1 as a communication axis between MNs and ECs. Using cell-specific knockout mice and in vitro assays, we demonstrate that removal of Sema3C in MNs, or its receptor PlexinD1 in ECs, results in premature and aberrant vascularization of MN columns. Those vascular defects impair MN axon exit from the spinal cord. Impaired PlexinD1 signaling in ECs also causes MN maturation defects at later stages. This study highlights the importance of a timely and spatially controlled communication between MNs and ECs for proper spinal cord development.
Topics: Animals; Mice; Endothelial Cells; Motor Neurons; Spinal Cord; Signal Transduction; Axons; Mice, Knockout
PubMed: 36549270
DOI: 10.1016/j.neuron.2022.12.005 -
Seminars in Cell & Developmental Biology Jan 2019Motor neurons differentiate from progenitor cells and cluster as motor nuclei, settling next to the floor plate in the brain stem and spinal cord. Although precise... (Review)
Review
Motor neurons differentiate from progenitor cells and cluster as motor nuclei, settling next to the floor plate in the brain stem and spinal cord. Although precise positioning of motor neurons is critical for their functional input and output, the molecular mechanisms that guide motor neurons to their proper positions remain poorly understood. Here, we review recent evidence of motor neuron positioning mechanisms, highlighting situations in which motor neuron cell bodies can migrate, and experiments that show that their migration is regulated by axon guidance cues. The view that emerges is that motor neurons are actively trapped or restricted in static positions, as the cells balance a push in the dorsal direction by repulsive Slit/Robo cues and a pull in the ventral direction by attractive Netrin-1/DCC cues. These new functions of guidance cues are necessary fine-tuning to set up patterns of motor neurons at their proper positions in the neural tube during embryogenesis.
Topics: Axon Guidance; Cell Movement; Motor Neurons; Neurogenesis
PubMed: 29141180
DOI: 10.1016/j.semcdb.2017.11.016 -
Trends in Genetics : TIG Sep 2022Motor neurons are a remarkably powerful cell type in the central nervous system. They innervate and control the contraction of virtually every muscle in the body and... (Review)
Review
Motor neurons are a remarkably powerful cell type in the central nervous system. They innervate and control the contraction of virtually every muscle in the body and their dysfunction underlies numerous neuromuscular diseases. Some motor neurons seem resistant to degeneration whereas others are vulnerable. The intrinsic heterogeneity of motor neurons in adult organisms has remained elusive. The development of high-throughput single-cell transcriptomics has changed the paradigm, empowering rapid isolation and profiling of motor neuron nuclei, revealing remarkable transcriptional diversity within the skeletal and autonomic nervous systems. Here, we discuss emerging technologies for defining motor neuron heterogeneity in the adult motor system as well as implications for disease and spinal cord injury. We establish a roadmap for future applications of emerging techniques - such as epigenetic profiling, spatial RNA sequencing, and single-cell somatic mutational profiling to adult motor neurons, which will revolutionize our understanding of the healthy and degenerating adult motor system.
Topics: Adult; Amyotrophic Lateral Sclerosis; Animals; Disease Models, Animal; Humans; Motor Neurons; Spinal Cord; Transcriptome
PubMed: 35487823
DOI: 10.1016/j.tig.2022.03.016 -
Journal of Neurochemistry Mar 2021Long non-coding RNAs (lncRNAs) are RNAs that exceed 200 nucleotides in length and that are not translated into proteins. Thousands of lncRNAs have been identified with... (Review)
Review
Long non-coding RNAs (lncRNAs) are RNAs that exceed 200 nucleotides in length and that are not translated into proteins. Thousands of lncRNAs have been identified with functions in processes such as transcription and translation regulation, RNA processing, and RNA and protein sponging. LncRNAs show prominent expression in the nervous system and have been implicated in neural development, function and disease. Recent work has begun to report on the expression and roles of lncRNAs in motor neurons (MNs). The cell bodies of MNs are located in cortex, brainstem or spinal cord and their axons project into the brainstem, spinal cord or towards peripheral muscles, thereby controlling important functions such as movement, breathing and swallowing. Degeneration of MNs is a pathological hallmark of diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy. LncRNAs influence several aspects of MN development and disruptions in these lncRNA-mediated effects are proposed to contribute to the pathogenic mechanisms underlying MN diseases (MNDs). Accumulating evidence suggests that lncRNAs may comprise valuable therapeutic targets for different MNDs. In this review, we discuss the role of lncRNAs (including circular RNAs [circRNAs]) in the development of MNs, discuss how lncRNAs may contribute to MNDs and provide directions for future research.
Topics: Animals; Humans; Motor Neuron Disease; Motor Neurons; RNA, Long Noncoding
PubMed: 32970857
DOI: 10.1111/jnc.15198 -
Cellular and Molecular Life Sciences :... Nov 2016An expanded polyglutamine (polyQ) tract at the amino-terminus of the androgen receptor (AR) confers toxic properties responsible for neuronal and non-neuronal... (Review)
Review
An expanded polyglutamine (polyQ) tract at the amino-terminus of the androgen receptor (AR) confers toxic properties responsible for neuronal and non-neuronal degeneration in spinal and bulbar muscular atrophy (SBMA), one of nine polyQ expansion diseases. Both lower motor neurons and peripheral tissues, including skeletal muscle, are affected, supporting the notion that SBMA is not a pure motor neuron disease but a degenerative disorder of the neuromuscular system. Here, we review experimental evidence demonstrating both nerve and muscle degeneration in SBMA model systems and patients. We propose that polyQ AR toxicity targets these components in a time-dependent fashion, with muscle pathology predominating early and motor neuron loss becoming more significant at late stages. This model of pathogenesis has important therapeutic implications, suggesting that symptoms arising from degeneration of nerve or muscle predominate at different points and that directed interventions targeting these components will be variably effective depending upon disease progression.
Topics: Animals; Humans; Motor Neurons; Muscle, Skeletal; Nerve Degeneration; Neuromuscular Diseases; Peptides; Receptors, Androgen
PubMed: 27188284
DOI: 10.1007/s00018-016-2275-1