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The Control of Schwann Cell Myelination During Development and After Nerve Injury

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The Control of Schwann Cell Myelination During Development and After Nerve Injury The control of Schwann cell myelination during development and after nerve injury Sheridan L. Roberts Submitted for Doctor of Philosophy November 2015 1 Copyright statement. This copy of the thesis has been supplied on condition that anyone who consults it is understood to recognise that its copyright rests with its author and that no quotation from the thesis and no information derived from it may be published without the author's prior consent. 2 AUTHOR'S DECLARATION The control of Schwann cell myelination during development and after nerve injury submitted by Sheridan Leona Roberts of the Peninsula Schools of Medicine and Dentistry to Plymouth University as a thesis for the degree of Doctor of Philosophy in November 2015 This thesis, printed or electronic format, is available for Library use on the understanding that it is copyright material and that no quotation from the thesis may be published without proper acknowledgement. I certify that all material in this thesis which is not my own work has been identified and that no unchanged or acknowledged material has previously been submitted and approved for the award of a degree by this or any other University. At no time during the registration for the degree of Doctor of Philosophy has the author been registered for any other University award without prior agreement of the Graduate Sub-Committee. Word count of main body of thesis: 62,767 words Signed: Date: 3 Acknowledgements Firstly I would like to thank David Parkinson for all the support and encouragement you have given me throughout my PhD study. David, you have enabled me to see the light at the end of the tunnel when I have found it difficult, your enthusiasm has inspired me and I couldn’t have wished for a better supervisor throughout this journey. It has been a pleasure to work alongside Xin-Peng, Thomas and Lauren in the laboratory; I would like to thank you all for making this experience enjoyable. I appreciate both the advice and support you have all given me, along with your patience and understanding when I’ve been running around the lab like a crazy person and have desperately needed your help. I would also like to thank Kayleigh for always being there to lend a helping hand, it has been great to have shared this rollercoaster ride with you, through times of woe and happiness, from start to finish. You have been a great friend. I would finally like to thank Simon, my Mum, Dad, Sister, Nan and Uncle Carl, who have done nothing but shower me with love and support, been there to listen to me, pointed me in the right direction and have always been there to make me smile. I truly couldn’t have gotten to the end without your constant support. 4 Sheridan Leona Roberts Title: The control of Schwann cell myelination during development and after nerve injury Abstract Schwann cells are the principal glial cell of the peripheral nervous system and are responsible for axon maintenance, regeneration and increasing saltatory conduction of neurons. Schwann cell differentiation and myelination is mediated by a core network of transcription factors and signalling pathways, which have been divided into two groups; positive and negative regulators. Sox10, NFATc4, Oct6, Krox20 and the ERK 1/2 signalling pathway have been characterised as positive regulators of Schwann cell differentiation and myelination; with Sox10 and Krox20 also playing critical roles in myelin maintenance. On the other hand, transcription factors cJun, Pax3, Id2 and signalling pathways Notch and p38 mitogen activated protein (MAP) kinases (MAPK) have been identified as negative regulators of Schwann cell differentiation and myelin formation. Recently, the HMG transcription factor Sox2 was identified as a negative regulator of Schwann cell myelination in vitro, however its role in Schwann cell myelination in vivo has not yet been studied. This study therefore aimed to examine the role of Sox2 overexpression in Schwann cells and how it effects Schwann cell differentiation and myelination during development and after injury. In addition, we aimed to investigate for the first time the specific role of p38α (the major isoform of p38 MAPK) in Schwann cell myelination in vivo, by generating Schwann cell specific p38α conditional knockout mice. Sox2 is highly expressed in immature Schwann cells, but is downregulated as Schwann cells being to mature and differentiate. This study shows that continued expression of Sox2 during development and after injury, impairs Schwann cell differentiation and myelination by directly downregulating the expression of two core transcription factors; Sox10 and Krox20, as well as myelin proteins, P0 and MBP. In addition, we observe that continued Sox2 expression significantly increases Schwann cell proliferation and maintains Schwann cells in an immature state. Unexpectedly, we also observed that continued Sox2 expression significantly increases the number of macrophages present in the nerves of Sox2 overexpressing mice at both P60 and 21 days post injury. Phenotypically, Sox2 overexpressing mice 5 show signs of a peripheral neuropathy and animals have impaired motor and sensory function. These findings confirm that Sox2 is a negative regulator of Schwann cell myelination and suggests that continued Sox2 expression is sufficient to drive the progressive development of a peripheral nerve disorder which may resemble Charcot-Marie-Tooth type 1 demyelinating neuropathy and congenital hypomyelinating neuropathy. As a negative regulator of Schwann cell myelination, activity of the p38 MAPK pathway has been shown to inhibit myelin formation in vitro and to also induce the Schwann cell injury response; by driving Schwann cell dedifferentiation and demyelination following injury. Here we show that specific removal of the p38α isoform in Schwann cells leads to an increase in myelin thickness at early developmental time-points, along with an elevated expression of myelin proteins, P0 and MBP. Further analysis following nerve injury revealed that removal of p38α results in an initial decrease in Schwann cell demyelination, yet improves axon remyelination at 21 days post injury. These results demonstrate the specific role of p38α in regulating Schwann cell myelination, and how it could be a direct therapeutic target for improving nerve repair after injury. 6 Table of Contents Abbreviations ......................................................................................................... 15 Chapter 1 Introduction ........................................................................................... 19 1.1 Structure of the myelin sheath ..................................................................... 22 1.2 Composition of myelin ................................................................................. 26 1.2.1 Compact myelin proteins ............................................................................. 26 1.2.2 Non-compact myelin proteins ...................................................................... 28 1.3 Schwann cell development .......................................................................... 29 1.4 Axonal myelination signalling ....................................................................... 34 1.5 Positive myelin regulators during Schwann cell development ..................... 43 1.5.1 Sox10 .......................................................................................................... 43 1.5.2 Oct 6 ............................................................................................................ 46 1.5.3 Krox20 ......................................................................................................... 46 1.6 Negative myelin regulators during Schwann cell development and in the injury response. ........................................................................................... 49 1.6.1 cJun ............................................................................................................. 49 1.6.2 Sox2 ............................................................................................................ 51 1.6.3 Notch ........................................................................................................... 52 1.6.4 ERK ............................................................................................................. 53 1.6.5 p38 MAPK ................................................................................................... 55 1.6.6 Sox4 ............................................................................................................ 56 1.6.7 Pax3, Id2, Egr1 and Egr3. ........................................................................... 56 1.7 Schwann cell demyelination, remyelination and repair ................................ 60 1.8 Differences between the PNS and CNS in nerve repair after injury ............. 63 1.9 Schwann cells in disease ............................................................................ 63 1.9.1 Peripheral neuropathies .............................................................................. 64 1.9.1.1 Charcot-Marie-Tooth disease ...................................................................... 64 1.9.2 Neurofibromatosis type 1 ............................................................................. 68 1.9.3 Neurofibromatosis type 2 ............................................................................. 68 1.10 Studying Schwann cell biology in vivo ......................................................... 69 1.10.1 Cre-LoxP
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