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UC San Diego UC San Diego Electronic Theses and Dissertations UC San Diego UC San Diego Electronic Theses and Dissertations Title Astrocyte activity modulated by S1P-signaling in a multiple sclerosis model Permalink https://escholarship.org/uc/item/2bn557vr Author Groves, Aran Publication Date 2015 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California UNIVERSITY OF CALIFORNIA, SAN DIEGO Astrocyte activity modulated by S1P-signaling in a multiple sclerosis model A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Neurosciences by Aran Groves Committee in charge: Professor Jerold Chun, Chair Professor JoAnn Trejo, Co-Chair Professor Jody Corey-Bloom Professor Mark Mayford Professor William Mobley 2015 The Dissertation of Aran Groves is approved, and it is acceptable in quality and form for publication on microfilm and electronically: Co-Chair Chair University of California, San Diego 2015 iii TABLE OF CONTENTS Signature Page ..................................................................................................... iii Table of Contents ................................................................................................. iv List of Figures ....................................................................................................... vi List of Tables ....................................................................................................... viii Acknowledgments ................................................................................................. ix Vita ....................................................................................................................... xiii Abstract of the Dissertation ................................................................................. xiv Chapter 1: Introduction .......................................................................................... 1 1.A. Fingolimod: direct CNS effects of sphingosine 1-phosphate receptor modulation and implications in multiple sclerosis therapy ................................ 1 1.B. Surveying for activity with immediate early genes ................................... 16 Chapter 2: Assessing the capabilities of c-Fos reporter mice to indicate EAE activity .................................................................................................................. 42 2.A. Introduction ............................................................................................ 42 2.B. Materials and Methods ........................................................................... 42 2.C. Results .................................................................................................... 45 2.D. Discussion .............................................................................................. 49 Chapter 3: Spatial and temporal properties of astrocyte activation in EAE and correlation to clinical severity with modulation of S1P receptors ......................... 59 3.A. Introduction ............................................................................................ 59 3.B. Materials and Methods ........................................................................... 60 3.C. Results .................................................................................................... 63 iv 3.D. Discussion .............................................................................................. 66 Chapter 4: Functional properties of astrocyte activity during acute EAE with modulation of S1P receptors ............................................................................... 80 4.A. Introduction ............................................................................................ 80 4.B. Materials and Methods ........................................................................... 81 4.C. Results .................................................................................................... 83 4.D. Discussion .............................................................................................. 86 Chapter 5: Concluding remarks and future directions ....................................... 116 v LIST OF FIGURES Chapter 1: Introduction Figure 1.1. Distribution and functions of S1P receptor subtypes in central nervous system cells ......................................................................................................... 20 Figure 1.2. Summary of the effects of fingolimod treatment on different cells in the central nervous system ........................................................................................ 21 Figure 1.3. The tetracycline transactivator system (tTA) under control of the c-Fos promoter allows persistent identification of active cells over extended and selected durations ................................................................................................ 22 Chapter 2: Assessing the capabilities of c-Fos reporter mice to indicate EAE activity Figure 2.1. EAE is inducible in TetTag mice ........................................................ 51 Figure 2.2. EAE induces robust c-Fos activity in the spinal cord ......................... 52 Figure 2.3. The onset of EAE clinical signs initiates increases in c-Fos activity .................................................................................................................. 53 Figure 2.4.1. Lymphocytes are c-Fos active in lymph nodes, but not in the spinal cord during acute EAE ......................................................................................... 54 Figure 2.4.2. Microglia are not c-Fos active in the spinal cord during acute EAE ...................................................................................................................... 55 Figure 2.4.3. Oligodendrocytes and oligodendrocyte precursor cells are not c-Fos active during acute EAE in the spinal cord .......................................................... 55 Figure 2.4.4. Few neurons are c-Fos activated during acute EAE ...................... 56 Figure 2.4.5. Astrocytes are the predominant c-Fos active cell-type in acute EAE ...................................................................................................................... 56 Chapter 3: Spatial and temporal properties of astrocyte activation in EAE and correlation to clinical severity with modulation of S1P receptors vi Figure 3.1. The TetTag c-Fos reporter mice have reduced EAE severity in astrocyte specific S1P1 knockouts and with fingolimod treatment during 5-dpo .. 69 Figure 3.2. Genetic removal of S1P1 on astroctyes or fingolimod treatment retains the prevalence of c-Fos activation in astrocytes during acute EAE ..................... 70 Figure 3.3. TetTag mice show the temporal and spatial progression of astrocyte c-Fos activation during acute EAE ....................................................................... 71 Figure 3.4. Astrocyte activation during 5-dpo occurs in similarly structured clusters, but at different frequencies in S1P1-CTRL, S1P1-AstKO, and S1P1- CTRL + fingolimod groups ................................................................................... 73 Figure 3.5. Astrocyte activation is correlated with disease severity during 5-dpo acute EAE ........................................................................................................... 75 Chapter 4: Functional properties of astrocyte activity during acute EAE with modulation of S1P receptors Figure 4.1. Total RNA isolated from EAE-activated astrocytes is full-length and yields normal cDNA library profiles ...................................................................... 90 Figure 4.4. Inclusions of introns from nucRNA does not affect the evaluation of transcription activity by RNA-seq ........................................................................ 93 Figure 4.5. The reduction of S1pr1 in S1P1-AstKO group indicates efficient astrocyte isolation and EAE-activated astrocytes show reduced c-Fos activity after 5-dpo ........................................................................................................... 94 Figure 4.8. Commonly altered transcripts between S1P1-AstKO and S1P1-CTRL + fingolimod, and S1P1-CTRL groups ................................................................ 108 vii LIST OF TABLES Chapter 4: Functional properties of astrocyte activity during acute EAE with modulation of S1P receptors Table 4.2. Fidelity of sequencing data from EAE-activated astrocytes from S1P1- CTRL, S1P1-AstKO, and S1P1-CTRL + fingolimod groups .................................. 91 Table 4.3. Sequencing libraries derived from nucRNA from EAE-activated astrocytes show characteristic mapping properties ............................................. 92 Table 4.6. Differentially expressed transcripts identified by RNA-seq that are significantly changed S1P1-CTRL and S1P1-AstKO groups ................................ 95 Table 4.7. Differentially expressed transcripts that are significantly changed S1P1-CTRL and S1P1-CTRL + fingolimod groups ............................................. 103 viii ACKNOWLEDGEMENTS I thank Dr. Jerold Chun for the challenge and opportunity to conduct this rewarding research in his laboratory. The talent and atmosphere he has imparted into his lab have provided the tools and motivation for taking on this challenging project and for not giving up when problems seemed insurmountable. I was reluctant to leave my comfort zone and Jerold aptly realized and instructed me that it
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