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ETH23721.Pdf Research Collection Doctoral Thesis The Importance of Clathrin-Mediated Endocytosis in Adult Myelinating Schwann Cells Author(s): Gerber, Daniel Paul Publication Date: 2016 Permanent Link: https://doi.org/10.3929/ethz-a-010735322 Rights / License: In Copyright - Non-Commercial Use Permitted This page was generated automatically upon download from the ETH Zurich Research Collection. For more information please consult the Terms of use. ETH Library ACHTUNG: ERSTE SETIE NICHT DRUCKEN (Druckbefehl von: 1-200) DISS. ETH No. 23721 The Importance of Clathrin-Mediated Endocytosis in Adult Myelinating Schwann Cells a thesis submitted to attain the degree of DOCTOR OF SCIENCES of ETH ZURICH (Dr. sc. ETH Zurich) presented by DANIEL PAUL GERBER MSc ETH Biology born 03.10.1987 citizen of Zurich (ZH) accepted on the recommendation of Prof. Dr. Ueli Suter (referee) Prof. Dr. Claire Jacob (co-referee) Prof. Dr. Bernd Wollscheid (co-referee) Dr. Axel Niemann (co-referee) 2016 Introduction 2 Summary Mutations in dynamin 2 (DNM2) have been reported to cause Charcot-Marie-Tooth (CMT) disease, the most prevalent hereditary neuropathy of the peripheral nervous system. The ubiquitously expressed dynamin 2 has a wide range of cellular functions, being involved in various forms of endocytosis, vesicular trafficking and cytoskeletal remodelling. However, its physiological role in the CMT-relevant cell types is poorly understood, which has made it difficult to understand the pathomechanisms leading to CMT. Hence, we generated a Schwann cell-specific inducible knockout mouse (Dnm2iko) to investigate the physiological role of Dnm2 in adult myelinating Schwann cells. Four weeks after induction, Dnm2iko mice developed a severe demyelinating phenotype with paraparesis followed by spontaneous recovery, a clinical course reminiscent of an acute inflammatory demyelinating polyneuropathy (AIDP), the most common subtype of Guillain-Barré-Syndrom (GBS). At a histological level, the demyelination was accompanied by a strong inflammatory response with a prominent macrophage infiltrate. Interestingly, pharmacological ablation of macrophages led to a delayed clinical recovery, thus pointing towards a beneficial role of these inflammatory cells. We than took advantage of a YFP-reporter mouse line to determine the identity of the demyelinating and remyelinating SCs. To our surprise we could show that demyelination in Dnm2iko mice was followed by apoptosis of all the recombined Schwann cells (70 % of all the SCs), and that the remaining 30 % non- recombined SCs were able to repopulate and remyelinate the entire nerve. Overall, these results underline the remarkable plasticity of SCs and show an absolute requirement of dynamin 2 for myelin integrity and survival of adult SCs. A recent study suggested that impaired clathrin-mediated endocytosis (CME) is the major contributing factor in the Dnm2-related forms of CMT. In order to assess the contribution of impaired CME to the observed phenotype in Dnm2iko mice, we generated Schwann cell-specific inducible knockout mice for the µ-subunit (AP2iko) of the adaptor protein complex 2 (AP-2), which is absolutely required for and exclusively involved in CME. In contrast to Dnm2iko, AP2iko mice did not develop an acute demyelinating neuropathy within the first months after recombination. Instead, aged mice developed a chronic peripheral neuropathy with features of de- and remyelination, the formation of outfoldings and onion bulbs, as well as secondary axonal loss. All of these are classical hallmarks of Charcot-Marie-Tooth disease. Finally, we found that the ablation of AP2µ2 or Dnm2 leads to an iron deficiency due to the impaired uptake of transferrin receptor, which could partially contribute to the observed demyelination. In conclusion, our data indicate that SCs rely on CME for long-term maintenance of peripheral nerves, whereas other functions of dynamin 2 are additionally required to ensure SC survival. Introduction 4 Zusammenfassung Spezifische Mutationen im Dynamin 2-Gen führen zu einer Charcot-Marie-Tooth (CMT) Neuropathie. Das ubiquitär exprimierte Dynamin 2 hat eine Vielzahl von Funktionen. Diese reichen von verschiedenen Formen der Endozytose über den intrazellulären Transport von Vesikeln bis hin zur Modulation des Zytoskeletts. Trotzdem ist über die Funktion von Dynamin 2 in denen für CMT relevanten Zelltypen wenig bekannt. Deswegen generierten wir eine induzierbare Knockout-Maus, welche es uns ermöglicht die Expression von Dynamin 2 spezifisch in Schwann Zellen zu inhibieren (Dnm2iko). Vier Wochen nach der Induktion entwickeln diese Mäuse eine starke, aber transiente Neuropathie. Der klinische Phänotyp hat viele Gemeinsamkeiten mit der akuten inflammatorischen demyelinisierenden Polyradikuloneuropathie (AIDP), der häufigsten Unterart des Guillain-Barré-Syndrom (GBS). Wir konnten zeigen, dass die Schwann Zellen in den Dnm2iko Mäusen nach der Demyelinisierung in Apoptose gehen. Dieser Prozess wird von einer starken Entzündungsreaktion begleitet. Die hierbei infiltrierenden Makrophagen sind vorteilhaft für die Regeneration der beschädigten Nerven. Erstaunlicherweise kann der beobachtete Verlust von 70 % aller Schwann Zellen (alle rekombinierten Schwann Zellen) von den 30% nicht-rekombinierten Zellen kompensiert werden. Dies führt innerhalb von zwei Wochen nach der stärksten Beeinträchtigung zur Erholung der betroffenen Mäuse. Zusammenfassend können wir sagen, dass Dynamin 2 absolut notwendig für die Erhaltung der Myelinschicht, sowie für das Überleben von adulten myelinisierenden Schwann Zellen ist. Eine kürzlich erschienene Studie hat gezeigt, dass eine beeinträchtigte Clathrin-vermittelte Endozytose (CME) die Hauptursache für die von mutiertem Dynamin 2 hervorgerufene CMT ist. Um eine Verknüpfung des in den Dnm2iko Mäusen beobachteten Phänotyps mit einer beeinträchtigten CME herzustellen, haben wir eine weitere Knockout-Maus generiert. Hierbei wurde die µ-Untereinheit des Adaptorproteinkomplexes 2 (AP-2) spezifisch in adulten myelinisierenden Schwann Zellen abladiert (AP2iko). AP-2 ist ausschliesslich und exklusiv an CME beteiligt. Im Gegensatz zu den Dnm2iko entwickeln AP2iko Mäuse während der ersten Monate keine transiente Neuropathie. Stattdessen manifestiert sich in gealterten Mäusen eine chronische periphere Neuropathie. In der Pathologie offenbarten sich die klassischen Eigenschaften einer CMT, wie eine De- und Remyelinisierung, die Bildung von Outfoldings und Onion-Bulbs, sowie sekundärer Axonverlust. Weiter konnten wir zeigen, dass der Verlust von AP2µ2 oder Dnm2 aufgrund der fehlenden CME zu einem Eisenmangel führt. Dieser Eisenmangel könnte zu der beobachteten Demyelinisierung beitragen. Abschliessend können wir sagen, dass der Phänotyp in den Dnm2iko Mäusen nicht ausschliesslich auf eine verminderte CME zurück zu führen ist. Dennoch führt der Verlust von CME in Schwann Zellen zu einer mit CMT vergleichbaren Neuropathie. Introduction Table of Contents 1 Introduction .............................................................................................................................. 1 1.1 The Vertebrate Peripheral Nervous System and its Myelin ......................................................... 1 1.2 The Origin and Development of Schwann Cells ........................................................................... 2 1.3 The Process of De- and Remyelination in the PNS ....................................................................... 3 1.3.1 Wallerian Degeneration ....................................................................................................... 6 1.3.2 Charcot-Marie-Tooth Neuropathy........................................................................................ 7 1.3.3 Inflammatory Neuropathies ................................................................................................. 9 1.4 The Dynamin Superfamily .......................................................................................................... 10 1.5 Dynamin 2 ................................................................................................................................... 11 1.6 Cellular Functions of Dynamin 2 ................................................................................................. 12 1.7 Dynamin 2 in Disease ................................................................................................................. 13 1.8 The Heterotetrameric Adaptor Complex Family ........................................................................ 14 1.9 The Adaptor Protein Complex 2 ................................................................................................. 15 1.10 Clathrin-Mediated Endocytosis .................................................................................................. 16 1.11 Iron ............................................................................................................................................. 17 1.12 Objective of the Study ................................................................................................................ 19 2 Results ..................................................................................................................................... 21 2.1 SC-Specific Ablation of Dynamin 2 in Adult Mice Results in a Remitting Neuropathy ............... 21 2.1.1 Acute De- and Remyelination upon Dynamin 2 Ablation ................................................... 22 2.1.2 Ablation of Dynamin 2 Causes Schwann Cell Dedifferentiation
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