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Integrin Expression in the Mouse Vestibular System

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Integrin Expression in the Mouse Vestibular System Integrin Expression in the Mouse Vestibular System Nicole Jennie Stanley Ear Institute University College London A thesis submitted for the degree of Doctor of Philosophy April 2013 1 Declaration I, Nicole Stanley, confirm that the work presented in this thesis is my own. Where information or assistance has been derived from other sources, I confirm that this has been indicated in the thesis. 2 Acknowledgements I would like to begin by thanking my supervisors Ruth and Andy for everything they have done for me as their PhD student which has culminated in the completion of this thesis. You have each always been ready to offer assistance and advice throughout my research, in so many different ways I couldn’t possibly describe them all here. Ruth has been instrumental in helping me learn all I needed to know about culturing utricles. I am very grateful to have had the support of your experience during this PhD. I have also appreciated Andy’s enthusiasm and encouragement – it is always good to have someone to remind you of what you have achieved, particularly when experiments are not going your way. I will miss working with you both very much indeed (and Andy is going to have to find somebody else with good hearing to test the click box on!). I wish you both, and the rest of the research group (especially Kiran who is going to carry ‘integrin torch’ once I have left), every success for the future. I would also like to thank Sally for her invaluable assistance with the molecular aspects of my project, since I had no real experience of this kind of lab work. Thank you for being patient and listening to all my many, many questions. An additional thank you must go to Deafness Research UK for the funding of my PhD studentship. The faces at the Ear Institute have been ever changing throughout my time as a PhD student. I would like to thank the back office crew, especially John and Elena, for making me feel welcome right from the start. I will miss the ‘in-jokes,’ Capital-FM Friday dancing and carving pumpkins at Halloween a lot. Thank you to Elena for all the ‘guy/relationships’ talk and for accommodating me on your sofa so I could be a part of after-work fun when I wasn’t living in London. John, who is forever in my debt since it was me that contained the cockroach that invaded the bathroom on our Californian adventure (although we did leave it there for the cleaners to deal with, oops!), I will miss having someone to keep me occupied during solution changes etc in the lab, and our attempts to communicate about our experiments only in bad GCSE French. I hope you have forgiven me for my less than perfect navigational skills in the US; I don’t think I can blame the map for my intermittent inability to get left and right correct! There are so many other people, too many to mention individually in case I forget someone, at the institute who have been around in the lab to ask questions or a share a friendly word, plus there was never a shortage of friendly faces to sit in the atrium with for lunch or have a tea-break to commiserate another failed cloning experiment. I can 3 safely say that the friendliness and social nature of the people who have worked at the Ear Institute have made it the most enjoyable place to have worked at for the past 5 years. I couldn’t write these acknowledgements without thanking my incredible girls; the best group of friends that anyone could ask for. It is amazing that having met each other at secondary school (or infant school in some cases!) that we have stuck it out together through whatever personal trials and tribulations we each have had to face in our lives, as well as the good fun times – there’s been 2 gorgeous weddings already during the time I’ve been a PhD student and I don’t doubt that there’s plenty more scary grown-up ness to come! Having friends like you girls has been so important in keeping me going throughout this PhD. Love you all lots. My family have always supported me in everything I have done, this PhD being no exception. Thank you to my parents for everything you have done for me and for listening to me talk about my research successes and woes even when you really didn’t have a clue what I was babbling on about. Thanks also to, ‘the other one,’ otherwise known as my brother, Anton – I think we have looked after each other pretty well in the last few years. Whenever I have been home and visiting family, I have always appreciated their taking an interest and asking me how my PhD was going; thank you and lots of love to you all. I hope I have made you, and those who are no longer with us and missed greatly, proud of all my achievements. Nicole Stanley September 2012 4 Abstract The mammalian utricle has shown limited capacity for spontaneous regeneration of hair cells within a damaged sensory epithelium. In vivo and in vitro exposure of the tissue to ototoxic aminoglycosides has been utilised to induce hair cell loss, in order to study these regenerative events. The mammalian utricle is believed to regenerate hair cells by the direct transdifferentiation of supporting cells without a mitotic event. The cellular and molecular mechanisms behind this regenerative capability continue to be the subject of inner ear research. The integrin family of cell surface receptors are known for their key role in cellular adhesion, both to the extracellular matrix and to neighbouring cells. Studies of integrins have shown that they are also involved in numerous cellular processes including proliferation, differentiation and migration. They are therefore a likely candidate for involvement in the cellular events which underlie the regenerative ability demonstrated by the mammalian utricle. This study has identified a subset of the mammalian integrin subunits as being present in the normal adult mouse utricle. The identification of these integrins was achieved by both degenerate PCR and qPCR screening of utricular cDNA. Through immunohistochemistry, β1 and α6 have been shown to localise at the basement membrane of normal utricular tissue. Integrins β3 and β5 appear to be expressed within vestibular hair cells. Integrins β1, αV, β5, β3 and α6 are also present within the mesenchyme. The utricular macula of adult mice was utilised as an in vitro model in order to induce hair cell loss by gentamicin treatment and investigate integrin expression in the utricle during this process and subsequent regeneration. Relative quantification of qPCR data has indicated that a number of integrins including β1, αV and β3 show an increase in expression level at 4 days post treatment. Immunohistochemistry shows some changes in integrin localisation between 4 and 21 days post-gentamicin. 5 Table of Contents Acknowledgements ........................................................................................................... 3 Abstract ............................................................................................................................. 5 Table of Contents .............................................................................................................. 6 List of Figures ................................................................................................................. 12 List of Tables................................................................................................................... 15 Chapter 1: Introduction ................................................................................................... 16 1.1 Integrins ................................................................................................................. 17 1.1.1 Integrin Structure and Ligand Binding ........................................................... 18 Nomenclature ........................................................................................................... 18 Structure and Ligand Binding .................................................................................. 21 1.1.2 Integrin Activation: ‘Inside-Out’ Signalling................................................... 24 1.1.3 Integrin Signalling: ‘Outside-In’ .................................................................... 26 1.1.4 Integrins and Cell Adhesion ........................................................................... 27 Focal Adhesions ....................................................................................................... 27 Hemidesmosomes .................................................................................................... 29 1.1.5 Integrins in Repair, Regeneration and Wound Healing .................................. 30 1.2 The Mammalian Inner Ear..................................................................................... 32 1.2.1 The Mammalian Auditory System .................................................................. 32 1.2.2 The Mammalian Vestibular System ............................................................... 37 ................................................................................................................................. 41 1.2.3 Integrins and the Inner Ear .............................................................................. 41 1.2.4 Regeneration & Repair in the Mammalian Utricle ......................................... 43 1.3 Scope of the Thesis ................................................................................................ 48 Chapter 2: Materials and Methods .................................................................................. 50 2.1 Animals ................................................................................................................
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