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Genetic and Cell Biological Studies of Sarm1 in Zebrafish

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Genetic and Cell Biological Studies of Sarm1 in Zebrafish Genetic and Cell Biological studies of Sarm1 in Zebrafish Dissertation an der Fakultät für Biologie der Ludwig-Maximilians-Universität München Durchgeführt am Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt Vorgelegt von Weili Tian This work has been done in the laboratory of Dr. Hernán López-Schier at the Research Unit Sensory Biology and Organogenesis, Helmholtz Zentrum München (Munich, Germany) from November 2014 to September 2019. 1. Gutachter: Prof. Dr. Barbara Conradt 2. Gutachter: Prof. Dr. rer. nat. Anja Horn-Bochtler Tag der Einreichung: 17.11.2019 Tag der mündlichen Prüfung: 18.03.2020 Abstract The peripheral nerves that communicate skin, muscle and sensory organs with the brain must maintain functionality throughout life despite frequent stress and injury. Loss of integrity of peripheral neurons and associated glial cells is a common occurrence in severe neurological dysfunctions that include weakness, pain and loss of sensation. Therefore, protecting the nervous system from chronic effects of physical and chemical stress is a pressing clinical challenge. This has sparked intense efforts to exploit molecular inhibitors of axonal and glial destruction. Loss of function of the obligate pro-degenerative protein Sarm1 blocks axon degeneration across species. Thus, Sarm1 is an ideal target for clinical application aimed at reducing axonal degradation in humans. In my thesis, I addressed the impact of Sarm1 deficiency on the development of the peripheral nervous system and glial Schwann cells. Using zebrafish, I show that elimination of Sarm1 is compatible with neural homeostasis, and is glioprotective against chemotherapeutic agents after nerve injury. Specifically, I have discovered that Schwann cells are not essential for the maintenance of severed axons lacking Sarm1, which subsist well beyond the normal timeframe allowed by Sarm1 destructive activity. Moreover, in Sarm1-deficient animals, the axons that regenerate after nerve injury regain connectivity with peripheral synaptic targets to enable sensorimotor recovery, revealing that neural-circuit repair is not contingent upon the clearance of damaged axons. In addition, I discovered that the loss of Sarm1 increases Schwann-cell resistance to toxicity by diverse chemotherapeutic agents after nerve injury. Overall, my findings indicate that pharmacological interventions targeting Sarm1 are promising strategies to reduce chronic consequences of nerve injury. Abstrakt Die peripheren Nerven, die Haut, Muskeln und Sinnesorgane mit dem Gehirn verbinden, müssen trotz häufigem Stress und Verletzung lebenslang funktionsfähig bleiben. Der Verlust der Integrität von peripheren Neuronen und assoziierten Zellen, einschließlich Glia, tritt häufig bei schweren neurologischen Funktionsstörungen auf, zu denen Schwäche, Schmerzen und Sensibilitätsverlust gehören. Daher ist der Schutz des Nervensystems vor chronischen Auswirkungen von physischem und chemischem Stress eine dringende klinische Herausforderung. Dies hat intensive Bemühungen ausgelöst, molekulare Inhibitoren der axonalen und glialen Zerstörung einzusetzen. Der Funktionsverlust des pro-degenerativen Proteins Sarm1 blockiert Axondegeneration sowohl in Invertebraten als auch in Vertebraten. Somit ist Sarm1 ein ideales Ziel für die klinische Anwendung, um den axonalen Abbau beim Menschen zu verhindern. In dieser Arbeit untersuchte ich die Auswirkungen von Sarm1-Mangel auf die Entwicklung des peripheren Nervensystems und der Schwannschen Gliazellen. Im Zebrafisch Modellorganismus zeigte ich, dass die genetische Ausschaltung von Sarm1 mit der neuralen Homöostase vereinbar ist und gegen chemotherapeutische Wirkstoffe nach Nervenverletzungen glioprotektiv ist. Insbesondere habe ich herausgefunden, dass Schwann-Zellen, die nach Axonenabtrennung eliminiert werden, aber in Abwesenheit von Sarm1 bestehen bleiben, für die Aufrechterhaltung der abgetrennten Axonen nicht wesentlich sind. Darüber hinaus stellen die Axone, die sich nach einer Nervenverletzung regenerieren, beim Sarm1-defizienten Zebrafisch die Konnektivität mit peripheren synaptischen Zielen wieder her, um die Wiederherstellung der Sensomotorik mus zu ermöglichen. Außerdem entdeckte ich, dass der Verlust von Sarm1 die Toxizitätsresistenz von Schwann-Zellen durch verschiedene Chemotherapeutika nach einer Nervenverletzung erhöht. Insgesamt weisen meine Ergebnisse darauf hin, dass pharmakologische Interventionen gegen Sarm1 vielversprechende Strategien zur Verringerung der chronischen Folgen von Nervenverletzungen darstellen. Table of Contents .......................................................................................................... i List of Figures .............................................................................................................. iv List of Tables .............................................................................................................. vii List of Abbreviations .............................................................................................. viii 1. Introduction .............................................................................................................. 1 1.1 Zebrafish as a vertebrate model to study developmental neuroscience and neurological disorders ............................................................................................ 1 1.1.1 Genetic modification of zebrafish ...................................................................... 2 1.1.2 Zebrafish as a model for neuroscience and neurological disorders research ...... 4 1.2 Zebrafish lateral line (sensory nerve) .................................................................. 5 1.2.1 Lateral line development .................................................................................... 5 1.2.2 Lateral line as a nerve regeneration model for research .................................... 8 1.3 Neuron degeneration and regeneration ............................................................... 8 1.3.1 Axon degeneration (Wallerian degeneration) .................................................... 8 1.3.2 Axon regeneration ............................................................................................ 10 1.4 Schwann cells ........................................................................................................ 14 1.4.1 Schwann cells development ............................................................................. 14 1.4.2 Schwann cells in neuron injury ........................................................................ 15 1.4.3 Communication between Schwann cells and Axons ....................................... 17 1.5 Sarm1 .................................................................................................................... 18 1.5.1 Sarm1 in immunology ...................................................................................... 18 1.5.2 Sarm1 in neurobiology ..................................................................................... 19 1.5.3 Sarm1 in neuron degeneration ......................................................................... 20 1.5.4 Sarm1 in neuron pathology .............................................................................. 22 1.6 Chemotherapy and neuropathy .......................................................................... 23 1.6.1 Mechanism of CIPN ........................................................................................ 24 1.6.2 CIPN and Axon transport, axonal degeneration .............................................. 26 2. Aims .......................................................................................................................... 28 i 3. Materials and Methods ....................................................................................... 30 3.1 Zebrafish strains and husbandry ....................................................................... 30 3.2 List of chemicals and reagents ............................................................................ 30 3.3 List of plasmids and primers .............................................................................. 33 3.4 Plasmids construction .......................................................................................... 36 3.5 Sarm1 mutagenesis .............................................................................................. 37 3.6 Transgenic lines .................................................................................................... 41 3.7 Immunostaining ................................................................................................... 42 3.8 Intravital microscopy ........................................................................................... 44 3.9 Western blot assay ............................................................................................... 44 3.10 Laser microsurgery ............................................................................................ 46 3.11 Chemogenetic approach .................................................................................... 47 3.12 Electrophysiological recordings ........................................................................ 48 3.13 Behavioral assays ............................................................................................... 49 3.14 Quantification of mitochondrial density and motility .................................... 51 3.15 Calcium imaging and quantification ...............................................................
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