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A Micro-Scope on Intracellular Trafficking

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A Micro-Scope on Intracellular Trafficking A micro-scope on intracellular trafficking PhD Thesis in partial fulfillment of the requirements for the degree “Doctor of Natural Sciences (Dr. rer. nat.)” in the GGNB Program - Center of Molecular Physiology of the Brain at the Georg August University Göttingen, Faculty of Biology submitted by Christian Olendrowitz born in Königs Wusterhausen, Germany I hereby declare that I prepared the PhD thesis: “A micro-scope on intracellular trafficking” on my own and with no other sources and aids than quoted. __________________________________________ Christian Olendrowitz Göttingen, 10. May 2011 Thesis committee members: Dr. Stefan Eimer, ENI Göttingen Prof. Dr. Holger Stark, MPI-BPC Göttingen Dr. Silvio Rizzoli, ENI Göttingen Date of oral exam: 05.05.2011 ii Dedication for my family iii iv Acknowledgments First of all I would like to thank my supervisors Stefan Eimer and Tim Salditt for sharing their time, knowledge and enthusiasm for science in the last three years. Furthermore I would like to thank them for their patience and encouragement in times of need. Secondly I would like to thank my thesis committee members Silvio Rizzoli and Holger Stark for their interest and guidance over the last years, especially in the early phases of the thesis work. All of these mentors criticism was essential in showing me how established scientists outside of the field of cellular trafficking perceive my work and how I should thus present it in an intelligible fashion. I would also like to express my appreciation for all the members of the labs that I worked in during the last years. Special thanks in this regards are directed to the role model scientist Marija Sumakovic and Mandy Hannemann as well as the Lord of the Rabs Nikhil Sasidharan. I have to thank all of you for your friendship but also for your generous and self sacrificing support in the lab during the last years. As invaluable guides in the world of x-ray physics I have to furthermore thank André Beerlink, Matthias Bartels, Robin Wilke and Sven-Philip Krüger. Without anyone of you and your useful comments this thesis in its current form would not have become possible. Further thanks are addressed to our collaborating groups. I thank Bernard Lakowski for his support in the dpy-1 project but I would also like to thank Jon Audhya and Amber Schuh as well as Nektarios Tavernarakis and Nikos Kurtis whose project were not mentioned in this thesis. All of your projects have fascinated me and it was a pleasure to have worked with you. Final thanks are addressed to the helping hands in the labs, scientist as well as technicians. To all of those, around or far away, who have supported me throughout the last years with their friendship. I share venturesome memories with all of you for which I am grateful beyond any measure. In this respect especially to mention are: David and Biese; Lukas, Hannes and Eike; Nora, Katrin and Ling; Erin; Christoph and Larus; as well as old friends like Andreas, Todd, Shim, Darwin, Gary, Thomas, as well as, Rolf and Fia together with their families. v Last but not least I would like to thank my host family, my parents and grandparents for their unbroken support in the last years, as well as, Ulrike and her family. In this respect I would like to thank Ulrike especially for her unquestionable love and enduring patience. Thank you for keeping me sane and reminding me of the important things in life. vi Abstract The general aim of this thesis work is to gain an encompassing insight into the intracellular trafficking machinery of multicellular organisms. For this purpose, the previously well-described model organism Caenorhabdits elegans is analyzed in our studies, with a focus on the family of small Rab-GTPases. These Rab-proteins (RABs) are the central players that orchestrate all intracellular trafficking events. An introduction to the current understandings in this field of science is given in the introductory chapter I. This thesis work began with a morphological description and a behavioral characterization of mutants of all members of rab-gene (rab) family. The major technique used for this anatomic investigation on the cellular- and subcellular level was two- as well as three-dimensional electron microscopy of high- pressure frozen nematode with a near-native sample-preservation. An atlas comprising all morphological data together with the results of additional behavioral studies, is the ultimate outcome of this thesis work. Among the descriptions of several tissues and organelles, the findings that the Golgi shapes seems to adapt to the activity in a tissue-specific manner is of central importance as it suggests that intracellular transport processes must also be investigated in a tissue-specific fashion. The generated tissue- and Rab-Atlas, along with all related results, is presented in chapter III, while a detailed description of used materials and methods is given in chapter II. During the entire investigation a special focus was directed towards the ultra-fast trafficking events that ensure the transmission at synapses. To aid these studies, the image analysis tool XtraCOunt was generated during this thesis work in order to semi-automates the analysis of these trafficking studies. Chapter IV describes this tool along with all its features. In the atlas studies the rab-10 mutant was identified as potentially neuronally impaired. In chapter IV, this mutant is examined for its synaptic features and it has been found to resemble the rab-2 mutant alterations in dense-core vesicle biogenesis. XtraCOunt was conceived for the analysis of electron micrographs of nematode synapses but was shown to be applicable in a vast range of other trafficking studies. Current collaborating studies, using this tool, led to the understanding of the phenotype of Sydney Brenner's first described mutant dpy-1 (dumpy), whose cuticular components are not able to maintain their network integrity. The fundamental findings of this study are presented in chapter V. To overcome imaging-constrains presented by the mostly electron microscopic nature of my study, I have furthermore tested the possibility of studying high-pressure frozen specimen with x-rays. High resolution phase contrast imaging, holo-tomography as well as micro-fluorescence investigations were tested for their applicability, feasibility and limitations. Their underlying mathematical theory and the obtained experimental results are presented and discussed in chapter VI. The major results of these vii investigations is a full-worm-tomogram with subcellular resolution and a map of tissue-specific elemental distributions within worm thin-slices. The concluding chapter VII briefly summarizes the results of all performed investigations in the context with one another and their possible meaning for the intracellular trafficking community. viii able of content Table of contents Dedication....................................................................................................................................................iii Acknowledgments .........................................................................................................................................v Abstract........................................................................................................................................................vii Table of contents..........................................................................................................................................ix Motivation......................................................................................................................................................1 Chapter I. Introduction..................................................................................................................................3 1.1 Eukaryotes tightly regulate their intracellular transport..........................................................................................3 1.2 Fission of membranes is supported and driven by multimolecular coats............................................................5 1.3 Target-specific fusion of membranes is mediated via SNARE proteins .............................................................6 1.4 Rab-GTPases localize compartment-specific to establish trafficking routes ......................................................7 1.5 Rab-GTPases orchestrate trafficking through active recruitment of effectors.................................................10 1.6 Characterizing the entire Rab-family........................................................................................................................ 14 1.7 The craft of preserving biological specimen for electron microscopy...............................................................16 1.8 Project description...................................................................................................................................................... 20 1.9 Structure of the thesis................................................................................................................................................ 21 Chapter II. Material and Methods...............................................................................................................23 2.1. Chemicals and nematodes ....................................................................................................................................... 23 2.2. Biomolecular Methods.............................................................................................................................................
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