DOCSLIB.ORG

Gamma and Alpha Motor Neurons Distinguished by Expression of Transcription Factor Err3

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

Gamma and alpha motor neurons distinguished by expression of transcription factor Err3 Andreas Friesea, Julia A. Kaltschmidtb,1,2, David R. Ladlea,1,3, Markus Sigrista, Thomas M. Jessellb,4, and Silvia Arbera,5 aBiozentrum, Department of Cell Biology, University of Basel and Friedrich Miescher Institute for Biomedical Research, CH-4058 Basel, Switzerland; and bHoward Hughes Medical Institute, Departments of Neuroscience and Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10027 Contributed by Thomas M. Jessell, June 26, 2009 (sent for review June 4, 2009) Spinal motor neurons are specified to innervate different muscle Yet neurons within a single motor pool also exhibit further targets through combinatorial programs of transcription factor subtype distinctions. Most motor pools are composed of a expression. Whether transcriptional programs also establish finer mixture of fast and slow motor neurons (11)—two classes that aspects of motor neuron subtype identity, notably the prominent exhibit distinct profiles of activation, produce different degrees functional distinction between alpha and gamma motor neurons, of force during the process of muscle contraction (11), and show remains unclear. In this study, we identify DNA binding proteins distinct vulnerabilities in motor neuron disease (12). Arguably with complementary expression profiles in alpha and gamma the most prominent distinction between neurons within a motor motor neurons, providing evidence for molecular distinctions in pool, however, is the presence of alpha and gamma motor these two motor neuron subtypes. The transcription factor Err3 is neurons. Alpha and gamma motor neurons differ in morphology, expressed at high levels in gamma but not alpha motor neurons, as well as in their peripheral and central patterns of connectivity whereas the neuronal DNA binding protein NeuN marks alpha but (11). Alpha motor neurons predominate within motor pools and not gamma motor neurons. Signals from muscle spindles are innervate force-generating extrafusal muscle fibers at neuromus- needed to support the differentiation of Err3on/NeuNoff presump- cular junctions (13). Gamma motor neurons constitute approx- tive gamma motor neurons, whereas direct proprioceptive sensory imately one third of all motor neurons within a pool and input to a motor neuron pool is apparently dispensable. Together, innervate the intrafusal muscle fibers found in muscle spindles, these findings provide evidence that transcriptional programs where they modulate the sensitivity of muscle spindles to stretch define functionally distinct motor neuron subpopulations, even (13–16). Gamma and alpha motor neurons also differ profoundly within anatomically defined motor pools. with respect to their soma size and connectivity profile within the spinal cord. Alpha motor neurons have large cell bodies, and motor neuron ͉ spinal cord ͉ transcription factors most receive direct group Ia–derived proprioceptive sensory input (17), whereas gamma motor neurons have small cell bodies euronal diversity underlies many features of central nervous (13) and lack direct input from proprioceptive sensory afferents Nsystem (CNS) organization and function. Neurons located (18). Because almost every motor neuron pool includes gamma within different regions of the CNS typically exhibit distinct and alpha motor neurons, subtype diversification at this in- morphologies and patterns of connectivity that help to deter- trapool level is conceptually different from the broad target– mine their physiological functions. Within a single region, neu- based distinctions that correlate with motor neuron pools. rons that serve closely related functions can be further subdi- The fundamental distinctions in alpha and gamma motor vided, both anatomically and physiologically. The retina, for neuron connectivity and function pose the question of how this finer, intrapool, aspect of motor neuron specification is pro- example, contains multiple subclasses of ganglion and amacrine grammed. Can the principle of transcriptional specification of neurons that are distinguishable by position, patterns of den- motor neuron subtype be extended to the distinction between dritic arborization, and their role in visual processing (1, 2). gamma and alpha motor neurons, features that are independent Similarly, the cerebral cortex contains many local circuit inter- of the identity of the target muscle group? If so, do gamma and neurons, each with specialized anatomy, circuitry, and physiol- alpha motor neurons each possess defining molecular markers, ogy (3). Little is known, however, about how such fine distinc- or do gamma motor neurons simply lack certain of the genes that tions in CNS neuronal subtype identity and connectivity are define alpha motor neuron identity, and vice versa? How do assigned. gamma and alpha motor neurons acquire their diverse anatom- The spinal cord represents a region of the CNS where the diversity of neuronal subtypes has been shown to emerge as a consequence of the expression of intrinsic molecular determi- Author contributions: A.F., J.A.K., D.R.L., M.S., T.M.J., and S.A. designed research; A.F., nants, acting in a hierarchical manner to assign subtype identities J.A.K., D.R.L., M.S., and S.A. performed research; A.F., J.A.K., D.R.L., M.S., T.M.J., and S.A. to a generic set of motor neurons (4, 5). The motor neurons that analyzed data; and J.A.K., T.M.J., and S.A. wrote the paper. project to skeletal muscle targets can be subdivided into distinct The authors declare no conflict of interest. columnar subgroups, each projecting to a different target do- Freely available online through the PNAS open access option. main—axial, body wall, and limb targets. The lateral motor 1J.A.K. and D.R.L. contributed equally to this study. column (LMC) neurons that project their axons to limb muscles 2Present address: Developmental Biology Program, Sloan–Kettering Institute, New York, can be further subdivided into divisional and pool subclasses NY 10065. that, together, specify the pattern of target muscle connectivity 3Present address: Department of Neuroscience, Cell Biology, and Physiology, Wright State (4, 5). The sequential steps involved in controlling motor neuron University, Dayton, OH 45435. subtype identities and target projections are programmed 4To whom correspondence may be addressed at: Columbia University, Howard Hughes through the cell-type selectivity of transcription factor expres- Medical Institute, Departments of Neuroscience and Biochemistry and Molecular Biophys- ics, 701 W 168th Street, New York, NY 10032. E-mail: [email protected]. sion, notably members of the Hox, LIM, Nkx6, and ETS families 5To whom may should be addressed at: Biozentrum, Department of Cell Biology, University (6–10). Thus combinatorial programs of transcription factor of Basel, Klingelbergstrasse 70, 4065 Basel and Friedrich Miescher Institute for Biomedical expression appear to provide the fundamental logic of spinal Research, Maulbeerstrasse 66, 4058 Basel, Switzerland. E-mail: [email protected]. motor neuron diversification and connectivity to specific periph- This article contains supporting information online at www.pnas.org/cgi/content/full/ eral muscle targets. 0906809106/DCSupplemental. 13588–13593 ͉ PNAS ͉ August 11, 2009 ͉ vol. 106 ͉ no. 32 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0906809106 Downloaded by guest on September 26, 2021 ical and functional properties—through cell-intrinsic programs, A putative gamma MNs putative alpha MNs through the influence of peripheral signals, or by virtue of their population 1 population 2 central connectivity? Intriguingly, the muscle fiber targets of m=232.4, sd=50.2 m=776.6, sd=179.7 gamma and alpha motor neurons can be distinguished by tran- scription factor expression; the zinc-finger transcription factor 40 Egr3 and the ETS transcription factors Pea3 and Er81 are 30 sllec# expressed selectively by intrafusal muscle fibers (19–21). Defin- ing molecular markers that distinguish gamma and alpha motor 02010 neurons would provide a first step in addressing the develop- mental specification of intrapool motor neuron subtypes. In this study, we set out to determine whether gamma and 200 400 600 800 1000 1200 1400 alpha motor neurons in the spinal cord of the mouse are MN size: µm2 distinguishable on the basis of their profile of expression of transcription factors and other molecular markers. We uncov- NM/snotuob1Gv# ered two genes with complementary expression profiles in B 30 gamma and alpha motor neurons. Gamma motor neurons ex- 02010 press high levels of the orphan nuclear hormone receptor Err3 (22, 23) and lack expression of neuronal DNA binding protein NeuN (24). Conversely, alpha motor neurons are characterized by low or negligible levels of Err3 and high-level NeuN expres- 200 400 600 800 1000 1200 1400 sion. Mice deficient in muscle spindle differentiation exhibit a MN size: µm2 selective absence of Err3on/NeuNoff presumptive gamma motor neurons. These findings establish that gamma and alpha motor putative gamma MN putative alpha MN neurons are molecularly distinct, and extend the principle that spinal motor neuron subtype identity has its origins in hierar- C D chical programs of transcription factor expression, even within a 1tul single anatomically coherent motor pool. Gv NEUROSCIENCE Results TAh Anatomical Identification of Presumptive Gamma and Alpha Motor C Neurons. Within the mammalian spinal cord, gamma and alpha motor neurons can be distinguished by two main anatomical features.
Recommended publications
  • Neural Control of Movement: Motor Neuron Subtypes, Proprioception and Recurrent Inhibition

    Neural Control of Movement: Motor Neuron Subtypes, Proprioception and Recurrent Inhibition

    List of Papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals. I Enjin A, Rabe N, Nakanishi ST, Vallstedt A, Gezelius H, Mem- ic F, Lind M, Hjalt T, Tourtellotte WG, Bruder C, Eichele G, Whelan PJ, Kullander K (2010) Identification of novel spinal cholinergic genetic subtypes disclose Chodl and Pitx2 as mark- ers for fast motor neurons and partition cells. J Comp Neurol 518:2284-2304. II Wootz H, Enjin A, Wallen-Mackenzie Å, Lindholm D, Kul- lander K (2010) Reduced VGLUT2 expression increases motor neuron viability in Sod1G93A mice. Neurobiol Dis 37:58-66 III Enjin A, Leao KE, Mikulovic S, Le Merre P, Tourtellotte WG, Kullander K. 5-ht1d marks gamma motor neurons and regulates development of sensorimotor connections Manuscript IV Enjin A, Leao KE, Eriksson A, Larhammar M, Gezelius H, Lamotte d’Incamps B, Nagaraja C, Kullander K. Development of spinal motor circuits in the absence of VIAAT-mediated Renshaw cell signaling Manuscript Reprints were made with permission from the respective publishers. Cover illustration Carousel by Sasha Svensson Contents Introduction.....................................................................................................9 Background...................................................................................................11 Neural control of movement.....................................................................11 The motor neuron.....................................................................................12 Organization
  • ALS and Other Motor Neuron Diseases Can Represent Diagnostic Challenges

    ALS and Other Motor Neuron Diseases Can Represent Diagnostic Challenges

    Review Article Address correspondence to Dr Ezgi Tiryaki, Hennepin ALS and Other Motor County Medical Center, Department of Neurology, 701 Park Avenue P5-200, Neuron Diseases Minneapolis, MN 55415, [email protected]. Ezgi Tiryaki, MD; Holli A. Horak, MD, FAAN Relationship Disclosure: Dr Tiryaki’s institution receives support from The ALS Association. Dr Horak’s ABSTRACT institution receives a grant from the Centers for Disease Purpose of Review: This review describes the most common motor neuron disease, Control and Prevention. ALS. It discusses the diagnosis and evaluation of ALS and the current understanding of its Unlabeled Use of pathophysiology, including new genetic underpinnings of the disease. This article also Products/Investigational covers other motor neuron diseases, reviews how to distinguish them from ALS, and Use Disclosure: Drs Tiryaki and Horak discuss discusses their pathophysiology. the unlabeled use of various Recent Findings: In this article, the spectrum of cognitive involvement in ALS, new concepts drugs for the symptomatic about protein synthesis pathology in the etiology of ALS, and new genetic associations will be management of ALS. * 2014, American Academy covered. This concept has changed over the past 3 to 4 years with the discovery of new of Neurology. genes and genetic processes that may trigger the disease. As of 2014, two-thirds of familial ALS and 10% of sporadic ALS can be explained by genetics. TAR DNA binding protein 43 kDa (TDP-43), for instance, has been shown to cause frontotemporal dementia as well as some cases of familial ALS, and is associated with frontotemporal dysfunction in ALS. Summary: The anterior horn cells control all voluntary movement: motor activity, res- piratory, speech, and swallowing functions are dependent upon signals from the anterior horn cells.
  • Innovations Present in the Primate Interneuron Repertoire

    Innovations Present in the Primate Interneuron Repertoire

    Article Innovations present in the primate interneuron repertoire https://doi.org/10.1038/s41586-020-2781-z Fenna M. Krienen1,2 ✉, Melissa Goldman1,2, Qiangge Zhang2,3, Ricardo C. H. del Rosario2, Marta Florio1,2, Robert Machold4, Arpiar Saunders1,2, Kirsten Levandowski2,3, Heather Zaniewski2,3, Received: 19 July 2019 Benjamin Schuman4, Carolyn Wu3, Alyssa Lutservitz1,2, Christopher D. Mullally1,2, Nora Reed1,2, Accepted: 1 July 2020 Elizabeth Bien1,2, Laura Bortolin1,2, Marian Fernandez-Otero2,5, Jessica D. Lin2, Alec Wysoker2, James Nemesh2, David Kulp2, Monika Burns5, Victor Tkachev6,7,8, Richard Smith9,10, Published online: xx xx xxxx Christopher A. Walsh9,10, Jordane Dimidschstein2, Bernardo Rudy4,11, Leslie S. Kean6,7,8, Check for updates Sabina Berretta5,12,13, Gord Fishell2,14, Guoping Feng2,3 & Steven A. McCarroll1,2 ✉ Primates and rodents, which descended from a common ancestor around 90 million years ago1, exhibit profound diferences in behaviour and cognitive capacity; the cellular basis for these diferences is unknown. Here we use single-nucleus RNA sequencing to profle RNA expression in 188,776 individual interneurons across homologous brain regions from three primates (human, macaque and marmoset), a rodent (mouse) and a weasel (ferret). Homologous interneuron types—which were readily identifed by their RNA-expression patterns—varied in abundance and RNA expression among ferrets, mice and primates, but varied less among primates. Only a modest fraction of the genes identifed as ‘markers’ of specifc interneuron subtypes in any one species had this property in another species. In the primate neocortex, dozens of genes showed spatial expression gradients among interneurons of the same type, which suggests that regional variation in cortical contexts shapes the RNA expression patterns of adult neocortical interneurons.
  • Spinal Cord Organization

    Spinal Cord Organization

    Lecture 4 Spinal Cord Organization The spinal cord . Afferent tract • connects with spinal nerves, through afferent BRAIN neuron & efferent axons in spinal roots; reflex receptor interneuron • communicates with the brain, by means of cell ascending and descending pathways that body form tracts in spinal white matter; and white matter muscle • gives rise to spinal reflexes, pre-determined gray matter Efferent neuron by interneuronal circuits. Spinal Cord Section Gross anatomy of the spinal cord: The spinal cord is a cylinder of CNS. The spinal cord exhibits subtle cervical and lumbar (lumbosacral) enlargements produced by extra neurons in segments that innervate limbs. The region of spinal cord caudal to the lumbar enlargement is conus medullaris. Caudal to this, a terminal filament of (nonfunctional) glial tissue extends into the tail. terminal filament lumbar enlargement conus medullaris cervical enlargement A spinal cord segment = a portion of spinal cord that spinal ganglion gives rise to a pair (right & left) of spinal nerves. Each spinal dorsal nerve is attached to the spinal cord by means of dorsal and spinal ventral roots composed of rootlets. Spinal segments, spinal root (rootlets) nerve roots, and spinal nerves are all identified numerically by th region, e.g., 6 cervical (C6) spinal segment. ventral Sacral and caudal spinal roots (surrounding the conus root medullaris and terminal filament and streaming caudally to (rootlets) reach corresponding intervertebral foramina) collectively constitute the cauda equina. Both the spinal cord (CNS) and spinal roots (PNS) are enveloped by meninges within the vertebral canal. Spinal nerves (which are formed in intervertebral foramina) are covered by connective tissue (epineurium, perineurium, & endoneurium) rather than meninges.
  • Lancl1 Promotes Motor Neuron Survival and Extends the Lifespan of Amyotrophic Lateral Sclerosis Mice

    Lancl1 Promotes Motor Neuron Survival and Extends the Lifespan of Amyotrophic Lateral Sclerosis Mice

    Cell Death & Differentiation (2020) 27:1369–1382 https://doi.org/10.1038/s41418-019-0422-6 ARTICLE LanCL1 promotes motor neuron survival and extends the lifespan of amyotrophic lateral sclerosis mice 1 1 1 1 1 1 1 Honglin Tan ● Mina Chen ● Dejiang Pang ● Xiaoqiang Xia ● Chongyangzi Du ● Wanchun Yang ● Yiyuan Cui ● 1,2 1 1,3 4 4 3 1,5 Chao Huang ● Wanxiang Jiang ● Dandan Bi ● Chunyu Li ● Huifang Shang ● Paul F. Worley ● Bo Xiao Received: 19 November 2018 / Revised: 3 September 2019 / Accepted: 6 September 2019 / Published online: 30 September 2019 © The Author(s) 2019. This article is published with open access Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons. Improving neuronal survival in ALS remains a significant challenge. Previously, we identified Lanthionine synthetase C-like protein 1 (LanCL1) as a neuronal antioxidant defense gene, the genetic deletion of which causes apoptotic neurodegeneration in the brain. Here, we report in vivo data using the transgenic SOD1G93A mouse model of ALS indicating that CNS-specific expression of LanCL1 transgene extends lifespan, delays disease onset, decelerates symptomatic progression, and improves motor performance of SOD1G93A mice. Conversely, CNS-specific deletion of fl 1234567890();,: 1234567890();,: LanCL1 leads to neurodegenerative phenotypes, including motor neuron loss, neuroin ammation, and oxidative damage. Analysis reveals that LanCL1 is a positive regulator of AKT activity, and LanCL1 overexpression restores the impaired AKT activity in ALS model mice. These findings indicate that LanCL1 regulates neuronal survival through an alternative mechanism, and suggest a new therapeutic target in ALS.
  • GDE2 Regulates Subtype-Specific Motor Neuron Generation Through

    GDE2 Regulates Subtype-Specific Motor Neuron Generation Through

    Neuron Article GDE2 Regulates Subtype-Specific Motor Neuron Generation through Inhibition of Notch Signaling Priyanka Sabharwal,1 Changhee Lee,1 Sungjin Park,1 Meenakshi Rao,1,2 and Shanthini Sockanathan1,* 1The Solomon Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, PCTB1004, 725 N. Wolfe Street, Baltimore, MD 21205, USA 2Present address: Department of Pediatrics, Children’s Hospital Boston, 300 Longwood Avenue, Boston, MA 02115, USA *Correspondence: [email protected] DOI 10.1016/j.neuron.2011.07.028 SUMMARY which is innervated by specific groups of motor neurons. Indi- vidual motor neuron groups are highly organized in terms of their The specification of spinal interneuron and motor cell body distribution, projection patterns, and function and neuron identities initiates within progenitor cells, consist of force-generating alpha motor neurons that innervate while motor neuron subtype diversification is regu- extrafusal muscle fibers and stretch-sensitive gamma motor lated by hierarchical transcriptional programs imple- neurons that innervate intrafusal muscle fibers of the muscle mented postmitotically. Here we find that mice lack- spindles (Dasen and Jessell, 2009; reviewed in Kanning et al., ing GDE2, a six-transmembrane protein that triggers 2010). The integration of input from both alpha and gamma motor neurons is essential for coordinated motor movement to motor neuron generation, exhibit selective losses occur (Kanning et al., 2010). of distinct motor neuron subtypes, specifically in How is diversity engendered in developing motor neurons? defined subsets of limb-innervating motor pools All motor neurons initially derive from ventral progenitor cells that correlate with the loss of force-generating alpha that are specified to become Olig2+ motor neuron progenitors motor neurons.
  • 1. 2. A) Explain the Compositions of White Matter and Gray

    1. 2. A) Explain the Compositions of White Matter and Gray

    Tfy-99.2710 Introduction to the Structure and Operation of the Human Brain, fall 2015 Exercise 1 1. 2. a) Explain the compositions of white matter and gray matter. White matter consists of glial cells and myelinated axons. It does not contain the cell bodies of neurons and acts as a signal pathway for the gray matter regions of the central nervous system. Gray matter consists of glial cells and unmyelinated axons. It contains neuronal cell bodies. b) Explain shortly the structure of a neuron. Neurons can be divided into three main parts: the cell body or the soma, the dendrites and the axon. The dendrites act as neuronal antennas in that they receive incoming signals. The cell body functions as the information processing unit of the neuron, and is responsible for sending signals forward. The axon is the signal pathway of the neuron; the signals sent by the cell body are transmitted along the axon to the axon terminals located away from the cell body. Signal transfer is along the axon is aided by the myelin sheath that covers the axon. c) Explain: Tfy-99.2710 Introduction to the Structure and Operation of the Human Brain, fall 2015 Exercise 1 i) myelin Membrane that wraps around axons. Formed from glial support cells: oligodendrogolia in the central nervous system and Schwann cells in the peripheral nervous system. Myelin facilitates signal transfer along axons by allowing action potentials to skip between the nodes of Ranvier (saltatory conduction). ii) receptor Molecule specialized in receiving a chemical signal by binding a specific neurotransmitter.
  • Reduction of Ephrin-A5 Aggravates Disease Progression in Amyotrophic

    Reduction of Ephrin-A5 Aggravates Disease Progression in Amyotrophic

    Rué et al. Acta Neuropathologica Communications (2019) 7:114 https://doi.org/10.1186/s40478-019-0759-6 RESEARCH Open Access Reduction of ephrin-A5 aggravates disease progression in amyotrophic lateral sclerosis Laura Rué1,2 , Patrick Oeckl3, Mieke Timmers1,2, Annette Lenaerts1,2, Jasmijn van der Vos1,2, Silke Smolders1,2, Lindsay Poppe1,2, Antina de Boer1,2, Ludo Van Den Bosch1,2, Philip Van Damme1,2,4, Jochen H. Weishaupt3, Albert C. Ludolph3, Markus Otto3, Wim Robberecht1,4 and Robin Lemmens1,2,4* Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects motor neurons in the brainstem, spinal cord and motor cortex. ALS is characterized by genetic and clinical heterogeneity, suggesting the existence of genetic factors that modify the phenotypic expression of the disease. We previously identified the axonal guidance EphA4 receptor, member of the Eph-ephrin system, as an ALS disease-modifying factor. EphA4 genetic inhibition rescued the motor neuron phenotype in zebrafish and a rodent model of ALS. Preventing ligands from binding to the EphA4 receptor also successfully improved disease, suggesting a role for EphA4 ligands in ALS. One particular ligand, ephrin-A5, is upregulated in reactive astrocytes after acute neuronal injury and inhibits axonal regeneration. Moreover, it plays a role during development in the correct pathfinding of motor axons towards their target limb muscles. We hypothesized that a constitutive reduction of ephrin-A5 signalling would benefit disease progression in a rodent model for ALS. We discovered that in the spinal cord of control and symptomatic ALS mice ephrin-A5 was predominantly expressed in neurons.
  • The Myelin-Forming Cells of the Nervous System (Oligodendrocytes and Schwann Cells)

    The Myelin-Forming Cells of the Nervous System (Oligodendrocytes and Schwann Cells)

    The Myelin-Forming Cells of the Nervous System (oligodendrocytes and Schwann cells) Oligodendrocyte Schwann Cell Oligodendrocyte function Saltatory (jumping) nerve conduction Oligodendroglia PMD PMD Saltatory (jumping) nerve conduction Investigating the Myelinogenic Potential of Individual Oligodendrocytes In Vivo Sparse Labeling of Oligodendrocytes CNPase-GFP Variegated expression under the MBP-enhancer Cerebral Cortex Corpus Callosum Cerebral Cortex Corpus Callosum Cerebral Cortex Caudate Putamen Corpus Callosum Cerebral Cortex Caudate Putamen Corpus Callosum Corpus Callosum Cerebral Cortex Caudate Putamen Corpus Callosum Ant Commissure Corpus Callosum Cerebral Cortex Caudate Putamen Piriform Cortex Corpus Callosum Ant Commissure Characterization of Oligodendrocyte Morphology Cerebral Cortex Corpus Callosum Caudate Putamen Cerebellum Brain Stem Spinal Cord Oligodendrocytes in disease: Cerebral Palsy ! CP major cause of chronic neurological morbidity and mortality in children ! CP incidence now about 3/1000 live births compared to 1/1000 in 1980 when we started intervening for ELBW ! Of all ELBW {gestation 6 mo, Wt. 0.5kg} , 10-15% develop CP ! Prematurely born children prone to white matter injury {WMI}, principle reason for the increase in incidence of CP ! ! 12 Cerebral Palsy Spectrum of white matter injury ! ! Macro Cystic Micro Cystic Gliotic Khwaja and Volpe 2009 13 Rationale for Repair/Remyelination in Multiple Sclerosis Oligodendrocyte specification oligodendrocytes specified from the pMN after MNs - a ventral source of oligodendrocytes
  • Cortex Brainstem Spinal Cord Thalamus Cerebellum Basal Ganglia

    Cortex Brainstem Spinal Cord Thalamus Cerebellum Basal Ganglia

    Harvard-MIT Division of Health Sciences and Technology HST.131: Introduction to Neuroscience Course Director: Dr. David Corey Motor Systems I 1 Emad Eskandar, MD Motor Systems I - Muscles & Spinal Cord Introduction Normal motor function requires the coordination of multiple inter-elated areas of the CNS. Understanding the contributions of these areas to generating movements and the disturbances that arise from their pathology are important challenges for the clinician and the scientist. Despite the importance of diseases that cause disorders of movement, the precise function of many of these areas is not completely clear. The main constituents of the motor system are the cortex, basal ganglia, cerebellum, brainstem, and spinal cord. Cortex Basal Ganglia Cerebellum Thalamus Brainstem Spinal Cord In very broad terms, cortical motor areas initiate voluntary movements. The cortex projects to the spinal cord directly, through the corticospinal tract - also known as the pyramidal tract, or indirectly through relay areas in the brain stem. The cortical output is modified by two parallel but separate re­ entrant side loops. One loop involves the basal ganglia while the other loop involves the cerebellum. The final outputs for the entire system are the alpha motor neurons of the spinal cord, also called the Lower Motor Neurons. Cortex: Planning and initiation of voluntary movements and integration of inputs from other brain areas. Basal Ganglia: Enforcement of desired movements and suppression of undesired movements. Cerebellum: Timing and precision of fine movements, adjusting ongoing movements, motor learning of skilled tasks Brain Stem: Control of balance and posture, coordination of head, neck and eye movements, motor outflow of cranial nerves Spinal Cord: Spontaneous reflexes, rhythmic movements, motor outflow to body.
  • Motor Neuron Disease Motor Neuron Disease

    Motor Neuron Disease Motor Neuron Disease

    Motor Neuron Disease Motor Neuron Disease • Incidence: 2-4 per 100 000 • Onset: usually 50-70 years • Pathology: – Degenerative condition – anterior horn cells and upper motor neurons in spinal cord, resulting in mixed upper and lower motor neuron signs • Cause unknown – 10% familial (SOD-1 mutation) – ? Related to athleticism Presentation • Several variations in onset, but progress to the same endpoint • Motor nerves only affected • May be just UMN or just LMN at onset, but other features will appear over time • Main patterns: – Amyotrophic lateral sclerosis – Bulbar presentaion – Primary lateral sclerosis (UMN onset) – Progressive muscular atrophy (LMN onset) Questions Wasting Classification • Amyotrophic Lateral Sclerosis • Progressive Bulbar Palsy • Progressive Muscular Atrophy • Primary Lateral Sclerosis • Multifocal Motor Neuropathy • Spinal Muscular Atrophy • Kennedy’s Disease • Monomelic Amyotrophy • Brachial Amyotrophic Diplegia El Escorial Criteria for Diagnosis Tongue fasiculations Amyotrophic lateral sclerosis • ‘Typical’ presentation (60%+) • Usually one limb initially – Foot drop – Clumsy weak hand – May complain of cramps • Gradual progression over months • May be some wasting at presentation • Usually fasiculations (often more widespread) • Brisk reflexes, extensor plantars • No sensory signs; MAY occasionally be mild symptoms • Relentless progression, noticable over weeks/ months Bulbar MND • Approximately 30% of cases • Onset with dysarthria, dysphagia • Bulbar and pseudobulbar symptoms • On examination – Dysarthria –
  • Olig2 Precursors Produce Abducens Motor Neurons and Oligodendrocytes in the Zebrafish Hindbrain

    Olig2 Precursors Produce Abducens Motor Neurons and Oligodendrocytes in the Zebrafish Hindbrain

    2322 • The Journal of Neuroscience, February 25, 2009 • 29(8):2322–2333 Cellular/Molecular Olig2ϩ Precursors Produce Abducens Motor Neurons and Oligodendrocytes in the Zebrafish Hindbrain Denise A. Zannino1,2 and Bruce Appel1,3 1Program in Neuroscience and 2Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee 37235, and 3Department of Pediatrics, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado 80045 During development, a specific subset of ventral spinal cord precursors called pMN cells produces first motor neurons and then oligo- dendrocyte progenitor cells (OPCs), which migrate, divide and differentiate as myelinating oligodendrocytes. pMN cells express the Olig2 transcription factor and Olig2 function is necessary for formation of spinal motor neurons and OPCs. In the hindbrain and midbrain, distinct classes of visceral, branchiomotor and somatic motor neurons are organized as discrete nuclei, and OPCs are broadly distributed. Mouse embryos deficient for Olig2 function lack somatic motor neurons and OPCs, but it is not clear whether this reflects a common origin for these cells, similar to spinal cord, or independent requirements for Olig2 function in somatic motor neuron and OPC develop- ment. We investigated cranial motor neuron and OPC development in zebrafish and found, using a combination of transgenic reporters and cell type specific antibodies, that somatic abducens motor neurons and a small subset of OPCs arise from common olig2ϩ neuroep- ithelial precursors in rhombomeres r5 and r6, but that all other motor neurons and OPCs do not similarly develop from shared pools of olig2ϩ precursors. In the absence of olig2 function, r5 and r6 precursors remain in the cell cycle and fail to produce abducens motor neurons, and OPCs are entirely lacking in the hindbrain.