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Vassilis E. Koliatsos - One of the best experts on this subject based on the ideXlab platform.
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neurotrophin 4 5 is a trophic factor for mammalian facial Motor Neurons
Proceedings of the National Academy of Sciences of the United States of America, 1994Co-Authors: Vassilis E. Koliatsos, Michelle H Cayouette, Richard E Clatterbuck, Lucy R. Berkemeier, Donald L Price, Arnon RosenthalAbstract:Abstract The survival of developing Motor Neurons depends on factors secreted from skeletal muscles and from cells within the central nervous system. Although several members of the nerve growth factor protein family [neurotrophins (NTs)] are able to maintain developing rat Motor Neurons in vitro, only the brain-derived neurotrophic factor has been shown to have significant effects on the survival of Motor Neurons in vivo. In the present study, we demonstrate that NT-4/5 also prevents injury-induced death of facial Motor Neurons in neonatal rats. Furthermore, facial Motor Neurons express a functional receptor for NT-4/5, whereas mRNA-encoding NT-4/5 can be detected in their environment throughout embryonic and postnatal life. Thus, both NT-4/5 and brain-derived neurotrophic factor may be physiological survival factors for facial Motor Neurons and may serve as therapeutic agents for Motor neuron disease.
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ventral root avulsion an experimental model of death of adult Motor Neurons
The Journal of Comparative Neurology, 1994Co-Authors: Vassilis E. Koliatsos, William L Price, Carlos A Pardo, Donald L PriceAbstract:The present study proposes a reproducible model of experimental degeneration of adult Motor Neurons in the rat. Avulsion of ventral roots in the adult lumbar cord transects Motor axons at the root exit and leads to retrograde cell death of 80% of Motor Neurons 2 weeks later; this result follows a series of retrograde changes, including chromatolysis, loss of transmitter phenotype, and accumulation of phosphorylated neurofilaments in perikarya. Glial cells recruited at the site of retrograde injury express both microglia-specific epitopes (as exemplified by OX-42 immunoreactivity) and macrophage-specific markers (e.g., ED-1 immunoreactivity). Macrophage-specific markers become particularly intense 7 days postaxotomy and provide additional evidence of active phagocytosis of injured Neurons. Ventral root avulsion is a very useful model for assessing mechanisms of Motor neuron death and testing the ability of trophic factors and other agents to preserve the phenotype and promote the survival of adult Motor Neurons in vivo.
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evidence that brain derived neurotrophic factor is a trophic factor for Motor Neurons in vivo
Neuron, 1993Co-Authors: Vassilis E. Koliatsos, John W Winslow, Michelle H Cayouette, Richard E Clatterbuck, Donald L PricesAbstract:Abstract The neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) act upon populations of Neurons that express specific receptors. The present study demonstrates that BDNF rescues Motor Neurons from degeneration and may also play a role in the normal physiology of these cells. BDNF is expressed in the local environment and in muscle targets of Motor Neurons; muscle expression is up-regulated by denervation. The a Motor Neurons express the gene encoding p145 trkB , a receptor involved in BDNF signal transduction, whereas a subset of Motor Neurons express p75 NGFR . BDNF is transported selectively to α Motor Neurons from skeletal muscles. Finally, BDNF prevents Motor neuron death in the axotomized facial nucleus of the neonatal rat. The effects of BDNF on Motor Neurons raise the possibility that some neurotrophins may be useful in treating patients with Motor neuropathies and amyotrophic lateral sclerosis.
Donald L Price - One of the best experts on this subject based on the ideXlab platform.
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neurotrophin 4 5 is a trophic factor for mammalian facial Motor Neurons
Proceedings of the National Academy of Sciences of the United States of America, 1994Co-Authors: Vassilis E. Koliatsos, Michelle H Cayouette, Richard E Clatterbuck, Lucy R. Berkemeier, Donald L Price, Arnon RosenthalAbstract:Abstract The survival of developing Motor Neurons depends on factors secreted from skeletal muscles and from cells within the central nervous system. Although several members of the nerve growth factor protein family [neurotrophins (NTs)] are able to maintain developing rat Motor Neurons in vitro, only the brain-derived neurotrophic factor has been shown to have significant effects on the survival of Motor Neurons in vivo. In the present study, we demonstrate that NT-4/5 also prevents injury-induced death of facial Motor Neurons in neonatal rats. Furthermore, facial Motor Neurons express a functional receptor for NT-4/5, whereas mRNA-encoding NT-4/5 can be detected in their environment throughout embryonic and postnatal life. Thus, both NT-4/5 and brain-derived neurotrophic factor may be physiological survival factors for facial Motor Neurons and may serve as therapeutic agents for Motor neuron disease.
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ventral root avulsion an experimental model of death of adult Motor Neurons
The Journal of Comparative Neurology, 1994Co-Authors: Vassilis E. Koliatsos, William L Price, Carlos A Pardo, Donald L PriceAbstract:The present study proposes a reproducible model of experimental degeneration of adult Motor Neurons in the rat. Avulsion of ventral roots in the adult lumbar cord transects Motor axons at the root exit and leads to retrograde cell death of 80% of Motor Neurons 2 weeks later; this result follows a series of retrograde changes, including chromatolysis, loss of transmitter phenotype, and accumulation of phosphorylated neurofilaments in perikarya. Glial cells recruited at the site of retrograde injury express both microglia-specific epitopes (as exemplified by OX-42 immunoreactivity) and macrophage-specific markers (e.g., ED-1 immunoreactivity). Macrophage-specific markers become particularly intense 7 days postaxotomy and provide additional evidence of active phagocytosis of injured Neurons. Ventral root avulsion is a very useful model for assessing mechanisms of Motor neuron death and testing the ability of trophic factors and other agents to preserve the phenotype and promote the survival of adult Motor Neurons in vivo.
Thomas M Jessell - One of the best experts on this subject based on the ideXlab platform.
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gamma and alpha Motor Neurons distinguished by expression of transcription factor err3
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Andreas Friese, Markus Sigrist, Julia A Kaltschmidt, David R Ladle, Thomas M Jessell, Silvia ArberAbstract:Spinal Motor Neurons are specified to innervate different muscle targets through combinatorial programs of transcription factor expression. Whether transcriptional programs also establish finer aspects of Motor neuron subtype identity, notably the prominent functional distinction between alpha and gamma Motor Neurons, remains unclear. In this study, we identify DNA binding proteins with complementary expression profiles in alpha and gamma Motor Neurons, providing evidence for molecular distinctions in these two Motor neuron subtypes. The transcription factor Err3 is expressed at high levels in gamma but not alpha Motor Neurons, whereas the neuronal DNA binding protein NeuN marks alpha but not gamma Motor Neurons. Signals from muscle spindles are needed to support the differentiation of Err3on/NeuNoff presumptive gamma Motor Neurons, whereas direct proprioceptive sensory input to a Motor neuron pool is apparently dispensable. Together, these findings provide evidence that transcriptional programs define functionally distinct Motor neuron subpopulations, even within anatomically defined Motor pools.
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astrocytes expressing als linked mutated sod1 release factors selectively toxic to Motor Neurons
Nature Neuroscience, 2007Co-Authors: Makiko Nagai, Thomas M Jessell, Hynek Wichterle, Tetsuya Nagata, Alcmene Chalazonitis, Serge PrzedborskiAbstract:Mutations in superoxide dismutase-1 (SOD1) cause a form of the fatal paralytic disorder amyotrophic lateral sclerosis (ALS), presumably by a combination of cell-autonomous and non–cell-autonomous processes. Here, we show that expression of mutated human SOD1 in primary mouse spinal Motor Neurons does not provoke Motor neuron degeneration. Conversely, rodent astrocytes expressing mutated SOD1 kill spinal primary and embryonic mouse stem cell–derived Motor Neurons. This is triggered by soluble toxic factor(s) through a Bax-dependent mechanism. However, mutant astrocytes do not cause the death of spinal GABAergic or dorsal root ganglion Neurons or of embryonic stem cell–derived interNeurons. In contrast to astrocytes, fibroblasts, microglia, cortical Neurons and myocytes expressing mutated SOD1 do not cause overt neurotoxicity. These findings indicate that astrocytes may play a role in the specific degeneration of spinal Motor Neurons in ALS. Identification of the astrocyte-derived soluble factor(s) may have far-reaching implications for ALS from both a pathogenic and therapeutic standpoint.
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directed differentiation of embryonic stem cells into Motor Neurons
Cell, 2002Co-Authors: Hynek Wichterle, Ivo Lieberam, Jeffery A Porter, Thomas M JessellAbstract:Inductive signals and transcription factors involved in Motor neuron generation have been identified, raising the question of whether these developmental insights can be used to direct stem cells to a Motor neuron fate. We show that developmentally relevant signaling factors can induce mouse embryonic stem (ES) cells to differentiate into spinal progenitor cells, and subsequently into Motor Neurons, through a pathway recapitulating that used in vivo. ES cell-derived Motor Neurons can populate the embryonic spinal cord, extend axons, and form synapses with target muscles. Thus, inductive signals involved in normal pathways of neurogenesis can direct ES cells to form specific classes of CNS Neurons.
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Motor neuron-derived retinoid signaling specifies the subtype identity of spinal Motor Neurons.
Cell, 1998Co-Authors: Shanthini Sockanathan, Thomas M JessellAbstract:Abstract The diversification of neuronal cell types in the vertebrate central nervous system depends on inductive signals provided by local organizing cell groups of both neural and nonneural origin. The influence of signals provided by postmitotic Neurons on the fate of Neurons born at subsequent development stages, however, remains unclear. We provide evidence that a retinoid-mediated signal provided by one subset of early-born spinal Motor Neurons imposes a local variation in the number of Motor Neurons generated at different axial levels and also specifies the identity of a later-born subset of Motor Neurons. Thus, in the vertebrate central nervous system the distinct fates of late-born Neurons may be acquired in response to signals provided by early-born Neurons.
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topographic organization of embryonic Motor Neurons defined by expression of lim homeobox genes
Cell, 1994Co-Authors: T Tsuchida, Thomas M Jessell, Monica Ensini, S B Morton, Mark Baldassare, Thomas Edlund, Samuel L PfaffAbstract:Abstract Motor Neurons located at different positions in the embryonic spinal cord innervate distinct targets in the periphery, establishing a topographic neural map. The topographic organization of Motor projections depends on the generation of subclasses of Motor Neurons that select specific paths to their targets. We have cloned a family of LIM homeobox genes in chick and show here that the combinatorial expression of four of these genes, Islet-1, Islet-2, Lim-1 , and Lim-3 , defines subclasses of Motor Neurons that segregate into columns in the spinal cord and select distinct axonal pathways. These genes are expressed prior to the formation of distinct Motor axon pathways and before Motor columns appear. Our results suggest that LIM homeobox genes contribute to the generation of Motor neuron diversity and may confer subclasses of Motor Neurons with the ability to select specific axon pathways, thereby initiating the topographic organization of Motor projections.
Arthur L Horwich - One of the best experts on this subject based on the ideXlab platform.
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transfer of pathogenic and nonpathogenic cytosolic proteins between spinal cord Motor Neurons in vivo in chimeric mice
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Eleanor V Thomas, Wayne A Fenton, Arthur L Horwich, James McgrathAbstract:Recent studies have reported spread of pathogenic proteins in the mammalian nervous system, but whether nonpathogenic ones spread is unknown. We initially investigated whether spread of a mutant amyotrophic lateral sclerosis-associated cytosolic superoxide dismutase 1 (SOD1) protein between Motor Neurons could be detected in intact chimeric mice. Eight-cell embryos from G85R SOD1YFP and G85R SOD1CFP mice were aggregated, and spinal cords of adult chimeric progeny were examined for Motor Neurons with cytosolic double fluorescence. By 3 mo of age, we observed extensive double fluorescence, including in amyotrophic lateral sclerosis-affected cranial nerve Motor nuclei but not in the relatively spared extraocular nuclei. Chimeras of nonpathogenic wtSOD1YFP and G85R SOD1CFP also exhibited double fluorescence. In a third chimera, mitochondrial mCherry did not transfer to G85R SOD1YFP Motor Neurons, suggesting that neither RNA nor organelles transfer, but mito-mCherry Neurons received G85R SOD1YFP. In a chimera of ChAT promoter-EGFP and mito-mCherry, EGFP efficiently transferred to mito-mCherry+ cells. Thus, nonpathogenic cytosolic proteins appear capable of transfer. During study of both the SOD1FP and EGFP chimeras, we observed fluorescence also in small cells neighboring the Motor Neurons, identified as mature gray matter oligodendrocytes. Double fluorescence in the G85R SOD1FP chimera and observation of the temporal development of fluorescence first in Motor Neurons and then in these oligodendrocytes suggest that they may be mediators of transfer of cytosolic proteins between Motor Neurons.
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absence of lipofuscin in Motor Neurons of sod1 linked als mice
Proceedings of the National Academy of Sciences of the United States of America, 2014Co-Authors: Urmi Bandyopadhyay, Maria Nagy, Wayne A Fenton, Arthur L HorwichAbstract:Lipofuscin, or aging pigment, is accreted as red autofluorescence in the lysosomes of Motor neuron cell bodies in the ventral horn of WT mice by 3 mo of age. Strikingly, in two presymptomatic ALS mouse strains transgenic for mutant human Cu/Zn superoxide dismutase (SOD1), G85R SOD1YFP and G93A SOD1, little or no lipofuscin was detected in Motor neuron cell bodies. Two markers of autophagy, sequestosome 1 (SQSTM1/p62) and microtubule-associated protein 1 light chain 3 (LC3), were examined in the Motor neuron cell bodies of G85R SOD1YFP mice and found to be reduced relative to WT SOD1YFP transgenic mice. To elucidate whether the autophagy/lysosome pathway was either impaired or hyperactive in Motor Neurons, chloroquine was administered to 3-mo-old G85R SOD1YFP mice to block lysosomal hydrolysis. After 2 wk, lipofuscin was now observed in Motor Neurons, and SQSTM1 and LC3 levels approached those of WT SOD1YFP mice, suggesting that the autophagy/lysosome pathway is hyperactive in Motor Neurons of SOD1-linked ALS mice. This seems to be mediated at least in part through the mammalian target of rapamycin complex 1 (MTORC1) pathway, because levels of Ser757-phosphorylated Unc-51-like kinase 1 (ULK1), an MTORC1 target, were greatly reduced in the G85R SOD1YFP Motor Neurons, correspondent to an activated state of ULK1 that initiates autophagy.
Kevin Eggan - One of the best experts on this subject based on the ideXlab platform.
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a stem cell based screening platform identifies compounds that desensitize Motor Neurons to endoplasmic reticulum stress
Molecular Therapy, 2019Co-Authors: Sebastian Thams, Luis A. Williams, Jackson Sandoe, Damian J Williams, Emily Rhodes Lowry, Mariehelene Larraufie, Krista Spiller, Phuong T Hoang, Elise Jiang, Kevin EgganAbstract:Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease selectively targeting Motor Neurons in the brain and spinal cord. The reasons for differential Motor neuron susceptibility remain elusive. We developed a stem cell-based Motor neuron assay to study cell-autonomous mechanisms causing Motor neuron degeneration, with implications for ALS. A small-molecule screen identified cyclopiazonic acid (CPA) as a stressor to which stem cell-derived Motor Neurons were more sensitive than interNeurons. CPA induced endoplasmic reticulum stress and the unfolded protein response. Furthermore, CPA resulted in an accelerated degeneration of Motor Neurons expressing human superoxide dismutase 1 (hSOD1) carrying the ALS-causing G93A mutation, compared to Motor Neurons expressing wild-type hSOD1. A secondary screen identified compounds that alleviated CPA-mediated Motor neuron degeneration: three kinase inhibitors and tauroursodeoxycholic acid (TUDCA), a bile acid derivative. The neuroprotective effects of these compounds were validated in human stem cell-derived Motor Neurons carrying a mutated SOD1 allele (hSOD1A4V). Moreover, we found that the administration of TUDCA in an hSOD1G93A mouse model of ALS reduced muscle denervation. Jointly, these results provide insights into the mechanisms contributing to the preferential susceptibility of ALS Motor Neurons, and they demonstrate the utility of stem cell-derived Motor Neurons for the discovery of new neuroprotective compounds.
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Modeling ALS with Motor Neurons derived from human induced pluripotent stem cells
Nature Neuroscience, 2016Co-Authors: Samuel Sances, Joseph R. Klim, Kevin Eggan, Lucie I Bruijn, Siddharthan Chandran, Ritchie Ho, Matt R Livesey, Emily Lowry, Jeffrey D Macklis, David RushtonAbstract: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. In this Review, a collaboration of leading experts in amyotrophic lateral sclerosis (ALS) research present the state of the field regarding the use patient-derived induced pluripotent stem cells to generate Motor Neurons in vitro . Motor neuron characterization, including transcriptomics, molecular markers, neuron function and electrophysiology, are discussed in the context of maturation and disease.
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modeling als with Motor Neurons derived from human induced pluripotent stem cells
Nature Neuroscience, 2016Co-Authors: Samuel Sances, Joseph R. Klim, Kevin Eggan, Siddharthan Chandran, Matt R Livesey, Jeffrey D Macklis, David Rushton, Emily Rhodes Lowry, Lucie Bruijn, Cameron SadeghAbstract: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.
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How to make spinal Motor Neurons
Development, 2014Co-Authors: Brandi N. Davis-dusenbery, Luis A. Williams, Joseph R. Klim, Kevin EgganAbstract:All muscle movements, including breathing, walking, and fine Motor skills rely on the function of the spinal Motor neuron to transmit signals from the brain to individual muscle groups. Loss of spinal Motor neuron function underlies several neurological disorders for which treatment has been hampered by the inability to obtain sufficient quantities of primary Motor Neurons to perform mechanistic studies or drug screens. Progress towards overcoming this challenge has been achieved through the synthesis of developmental biology paradigms and advances in stem cell and reprogramming technology, which allow the production of Motor Neurons in vitro . In this Primer, we discuss how the logic of spinal Motor neuron development has been applied to allow generation of Motor Neurons either from pluripotent stem cells by directed differentiation and transcriptional programming, or from somatic cells by direct lineage conversion. Finally, we discuss methods to evaluate the molecular and functional properties of Motor Neurons generated through each of these techniques.
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conversion of mouse and human fibroblasts into functional spinal Motor Neurons
Cell Stem Cell, 2011Co-Authors: Esther Y Son, Jeremy S. Toma, Victor F. Rafuse, Brian J Wainger, Justin K Ichida, Clifford J Woolf, Kevin EgganAbstract:Summary The mammalian nervous system comprises many distinct neuronal subtypes, each with its own phenotype and differential sensitivity to degenerative disease. Although specific neuronal types can be isolated from rodent embryos or engineered from stem cells for translational studies, transcription factor-mediated reprogramming might provide a more direct route to their generation. Here we report that the forced expression of select transcription factors is sufficient to convert mouse and human fibroblasts into induced Motor Neurons (iMNs). iMNs displayed a morphology, gene expression signature, electrophysiology, synaptic functionality, in vivo engraftment capacity, and sensitivity to degenerative stimuli similar to those of embryo-derived Motor Neurons. We show that the converting fibroblasts do not transit through a proliferative neural progenitor state, and thus form bona fide Motor Neurons via a route distinct from embryonic development. Our findings demonstrate that fibroblasts can be converted directly into a specific differentiated and functional neural subtype, the spinal Motor neuron.