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Localization and Transport of Ribosomes in Axons of the Mammalian PNS and CNS

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Localization and Transport of Ribosomes in Axons of the Mammalian PNS and CNS Localization and transport of ribosomes in axons of the mammalian PNS and CNS Dissertation zur Erlangung des Grades „Doktor der Naturwissenschaften“ am Fachbereich Biologie der Johannes Gutenberg-Universität in Mainz Kerstin Müller geb. am 06. April 1986 in Würzburg Mainz, 2016 The present PhD thesis was conducted at the Institute of Microanatomy and Neurobiology, University Medical Center of the Johannes-Gutenberg University Mainz, from May 1st, 2011 until June 30th, 2016. Dekan: 1. Berichterstatter: 2. Berichterstatter: Tag der mündlichen Prüfung: 24.10.2016 D77 – Mainzer Dissertation Declaration I Declaration “I hereby declare that I wrote the dissertation submitted without any unauthorized external assistance and used only sources acknowledged in the work. All textual passages which are appropriated verbatim or para-phrased from published and unpublished texts as well as all information obtained from oral sources are duly indicated and listed in accordance with bibliographical rules. Moreover, I declare that this is a true copy of my thesis, and that this thesis has not been submitted for a higher degree to any other University or Institution. In carrying out this research, I complied with the rules of standard scientific practice as formulated in the statutes of Johannes Gutenberg-University Mainz to insure standard scientific practice.” Mainz, 05.07.2016 (Kerstin Müller) Abstract II Abstract In recent years, many studies have indicated that some neuronal cell types produce proteins not only in the cell body, but also locally in dendrites, especially at synaptic sites, and in the axon. Local axonal translation seems to be important for the maintenance and growth of the axon, for retrograde signaling, and for the regeneration of peripheral nervous system (PNS) axons after injury. It was shown that messenger RNAs (mRNAs) are transported in ribonucleoprotein particles (RNPs) and there is increasing evidence that their axonal localization is selective for specific mRNAs. Additionally, the presence of ribosomes in the axonal compartment has been reported and many studies assumed that they are likewise transported in RNPs from the neuronal cell body. Recently, however, glial cells were proposed as an alternative source of axonal ribosomes. Such a glia-to-axon transfer is believed to account for the increased ribosomal levels observed in PNS axons after injury and to support local protein synthesis for regeneration. The aim of the present study was to show that axonally localized ribosomes originate from the neuronal cell body in vivo, also upon injury. To visualize ribosomes, the ribosomal protein L4 (RPL4), a component of the large 60S subunit of the ribosomal complex, was labeled in a transgenic mouse line. ‘RiboTracker’ mice contained the fusion construct of RPL4 tagged with tandem dimer protein Tomato (tdTomato) downstream of a floxed stop cassette in the ROSA26 locus. Crossbreeding with mice expressing Cre recombinase under the calcium/calmodulin-dependent protein kinase II alpha (CamKIIα) or Advillin promoter led to the neuron-specific expression of L4-tdTomato as shown for central nervous system (CNS) hippocampal and cortical neurons (CamKIIα), as well as dorsal root ganglia (DRG) neurons (CamKIIα, Advillin). However, when focusing on axons, L4-tdTomato was neither detected in vitro nor in vivo, even though the staining with an antibody against the ribosomal protein L26 (RPL26) confirmed the presence of axonal ribosomes. In the case of PNS injury, increased axonal levels of RPL26-stained ribosomes were observed, but again, L4-tdTomato signals were not found in the sciatic nerve fibers. These findings led to the conclusion that ribosomes are not transported from the neuronal cell body to the axon. Paralleling experiments with recombinant adeno-associated virus (rAAV) that express RPL4 fused to enhanced green fluorescence protein (eGFP) in a neuron-specific way supported the in vitro data from neuronal RiboTracker-Cre mice. Based on the prior in vivo results, however, studies with rAAVs were not continued. Next, glial cells were reconsidered as an alternative source of axonal ribosomes. To investigate this hypothesis, RiboTracker mice were crossed with a glial Cre line driven by the 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNP) promoter. Satellite glia cells and Schwann cells in the PNS showed strong expression of the transgene, but some DRG neurons also contained L4-tdTomato. These neuronal subpopulations were similar to those in the neuron- Abstract III specific RiboTracker-Cre mice, therefore, axonal ribosomes were unlikely to originate from the neuronal cell body. In the sciatic nerve, occasional L4-tdTomato signals were detected in uninjured axons of the RiboTracker-CNP-Cre mice. Upon injury, a massive increase of axonally localized tagged ribosomes was observed, paralleling the findings of immunostaining with the anti-RPL26 antibody. Since increased axonal levels of L4-tdTomato were also observed distally to the lesion site, glial cells represent the only possible source of axonal ribosomes. This is the first study investigating the origin of axonal ribosomes in transgenic mice in vivo. Taken together, the results from the present work strongly support the hypothesis of a glia- to-axon transfer of ribosomes, and go even beyond this by providing evidence for Schwann cells being the exclusive source of axonal ribosomes in the peripheral nervous system. Zusammenfassung IV Zusammenfassung In den letzten Jahren haben viele Studien gezeigt, dass einige neuronale Zelltypen Proteine nicht nur in ihrem Zellkörper, sondern auch lokal in Dendriten, vor allem an Synapsen, und im Axon produzieren. Lokale Proteintranslation scheint für die Versorgung und das Wachstum des Axons, für retrograde Signalübertragung und für die Regeneration der Axone des peripheren Nervensystems (PNS) nach Verletzung wichtig zu sein. Es ist gezeigt worden, dass messenger RNAs (mRNAs) in Ribonukleoprotein-Partikeln (RNPs) transportiert werden und es gibt immer mehr Hinweise darauf, dass deren axonale Lokalisation für spezifische mRNAs selektiv ist. Zusätzlich ist berichtet worden, dass Ribosomen im axonalen Kompartiment vorhanden sind, und es wird angenommen, dass sie ebenfalls in RNPs vom neuronalen Zellkörper ausgehend transportiert werden. Kürzlich jedoch wurden Gliazellen als alternativer Ursprung axonaler Ribosomen vorgeschlagen. Man vermutet, dass dieser Glia- Axon Transfer für die erhöhten Ribosomenmengen, die in Axonen des PNS nach Verletzung beobachtet wurden, verantwortlich ist und dass er die lokale Proteinsynthese zur Regeneration unterstützt. Ziel dieser Studie war es zu zeigen, dass axonal vorkommende Ribosomen dem neuronalen Zellkörper in vivo entstammen, auch nach einer Verletzung. Um Ribosomen zu visualisieren wurde das ribosomale Protein L4 (RPL4), eine Komponente der großen 60S Untereinheit des ribosomalen Komplexes, in einer transgenen Mauslinie markiert. „RiboTracker“ Mäuse beinhalten das Fusionskonstrukt, bestehend aus dem mit dem Tandemdimer-Protein Tomato (tdTomato) markierten RPL4, hinter einer gefloxten Stopkassette im ROSA26Lokus. Kreuzung mit Mäusen, die die Cre-Rekombinase unter dem Promoter der Kalzium/Kalmodulin-abhängigen Kinase II alpha (CamKIIα) oder dem Advillin-Promoter exprimieren, führte zu einer neuronspezifischen Expression des L4-tdTomato, wie für hippokampale und kortikale Neurone des zentralen Nervensystems (CamKIIα) und für Neurone der dorsalen Wurzelganglien (engl. dorsal root ganglia, DRG; CamKIIα, Advillin) gezeigt wurde. Als jedoch die Axone näher betrachtet wurden, konnte L4-tdTomato weder in vitro noch in vivo detektiert werden, obwohl die Färbung mit dem Antikörper gegen das ribosomale Protein L26 (RPL26) das Vorhandensein axonaler Ribosomen bestätigt hatte. Bei einer Verletzung des PNS wurden erhöhte, axonale Mengen RPL26-gefärbter Ribosomen beobachten, jedoch wurden auch hier keine Signale des L4-tdTomatos in den Fasern des Ischiasnervs gefunden. Diese Ergebnisse führten zu der Schlussfolgerung, dass Ribosomen nicht vom neuronalen Zellkörper zum Axon transportiert werden. Parallelexperimente mit einem rekombinanten Adeno-assoziierten Virus (rAAV), welcher RPL4, das mit dem verstärkt grün fluoreszierendem Protein (engl. enhanced green fluorescent protein, eGFP) fusioniert ist, neuron-spezifisch exprimiert, unterstützen die in vitro-Daten der neuronalen RiboTracker- Zusammenfassung V Cre-Mäuse. Basierend auf den vorausgehenden in vivo-Ergebnissen, wurden die Studien mit rAAVs jedoch nicht weiterverfolgt. Als nächstes wurden die Gliazellen als alternativer Ursprung axonaler Ribosomen erneut in Betracht gezogen. Um dieser Hypothese nachzugehen, wurden RiboTracker-Mäuse mit der glialen Cre-Linie, die den Promoter der 2‘,3’-zyklisches Nukleotid 3‘-Phosphodiesterase (CNP) besitzt, verpaart. Mantelzellen und Schwannzellen des PNS zeigten eine starke Expression des Transgens, aber auch einige DRG-Neurone beinhalteten L4-tdTomato. Diese neuronalen Subpopulationen waren vergleichbar mit denen der neuronspezifischen RiboTracker-Cre-Mäuse. Daher ist es sehr unwahrscheinlich, dass axonale Ribosomen dem neuronalen Zellkörper entstammen. Im Ischiasnerv wurden vereinzelte L4-tdTomato Signale in unverletzten Axonen der RiboTracker-CNP-Cre-Mäuse entdeckt. Nach Verletzung wurde ein massiver Anstieg axonal-lokalisierter, markierter Ribosomen beobachtet, was den Ergebnissen der Immunfärbung mit dem anti-RPL26 Antikörper entsprach. Da erhöhte axonale Menge an L4-tdTomato auch distal zur Läsionsseite bemerkt wurden,
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