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Unravelling the Cell Adhesion Defect in Meckel-Gruber Syndrome

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Unravelling the Cell Adhesion Defect in Meckel-Gruber Syndrome Unravelling the Cell Adhesion Defect in Meckel-Gruber Syndrome Submitted by Benjamin Roland Alexander Meadows as a thesis for the degree of Doctor of Philosophy in Biological Sciences in September 2016 This thesis 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 material has previously been submitted and approved for the award of a degree by this or any other University. ……………………………………………………………… 1 2 Acknowledgements The first people who must be thanked are my fellow Dawe group members Kate McIntosh, Kat Curry, and half of Holly Hardy, as well as all past group members and Helen herself, who has always been a supportive and patient supervisor with a worryingly encyclopaedic knowledge of the human proteome. Some (in the end, distressingly small) parts of this project would not have been possible without my western blot consultancy team, including senior western blot consultant Joe Costello and junior consultants Afsoon Sadeghi-Azadi, Jack Chen, Luis Godinho, Tina Schrader, Stacey Scott, Lucy Green, and Lizzy Anderson. James Wakefield is thanked for improvising a protocol for actin co- sedimentation out of almost thin air. Most surprisingly, it worked. Special thanks are due to the many undergraduates who have contributed to this project, without whose hard work many an n would be low: Beth Hickton, Grace Howells, Annie Toynbee, Alex Oldfield, Leonie Hawksley, and Georgie McDonald. Peter Splatt and Christian Hacker are thanked for their help with electron microscopy. Karen Moore, Audrey Farbos, and Konrad Paszkiewicz from the Sequencing Service are acknowledged for their work which enabled the differential expression analysis which informed much of this project, and Kate Heesom (of the University of Bristol Proteomics Facility) is thanked for performing the TMT-MS. Jeremy Metz is acknowledged for his efforts to automate image analysis – I’m sorry Jeremy, but undergraduates work better than computers. From the Biomedical Physics group, C. Peter Winlove, Peter Petrov, Barbara Sarri, and Ellen Green are thanked for their help with micropipetting experiments and cell spreading analysis, and for their endless patience and generosity. I would especially like to acknowledge the members of Gero Steinberg’s group, including Yujiro Higuchi, Sreedhar Kilaru, Anna Shiel, Ewa Bielska, Natalie Clark, Martin Schuster, Yvonne Roger, Gero himself, and all others who taught me a huge amount when I was just starting in the lab. 3 I would like to thank my family, small as it is, for their support and/or forbearance, especially during the dangerous writing up time. Finally I would like to thank all current and past members of lab 211, which despite the occasional fire, broken floor, flood, asbestos warning, insect infestation, threat of excess cardboard, and outbreak of pregnancy, has been the best-run lab I have ever known. In particular Sam Mitchell, Andrena Ellis, Charli Mardon, and Andy Early are thanked for keeping the lab in check, in their own special ways. 4 Abstract Meckel-Gruber syndrome (MKS) is a universally lethal heritable human disease characterised by CNS malformations, cystic kidney, polydactyly, and liver fibrosis. MKS is classed as one of the ciliopathies due to its association with dysfunctional primary cilia, signalling organelles found on most cells in the human body. Some of the symptoms of MKS can be explained as a consequence of disrupted developmental signalling through the primary cilium, other defects are harder to explain, and evidence now exists for non-ciliary influences on ciliopathies. The nature of these influences, and the implications they may have for our understanding of ciliary function and the aetiology of MKS, remain unclear. In this thesis, defects in cell-extracellular matrix (ECM) interaction in MKS are investigated to determine whether MKS proteins have a role in this process, and if so, whether this role may be involved in MKS pathology. A combination of transcriptomic, proteomic, and cell imaging approaches are used to demonstrate that MKS patient cells produce a defective extracellular matrix, and that the MKS protein TMEM67 is present at the cell surface at sites of cell-ECM interaction. It is shown that the full-length TMEM67 protein is required for correct ECM morphology, and it is further shown that the abnormal extracellular matrix morphology in MKS cells underlies other defects, including failure to build cilia and alterations to the actin cytoskeleton. This represents the first set of causal relationships identified between the cellular defects in this complex disease. It is further shown that treatment with developmental signalling pathway antagonists can rescue these defects, potentially revealing a new avenue of therapeutic intervention for MKS. Finally, possible upstream defects are investigated that might underlie the ECM defect, 5 including alterations to cell spreading behaviour and cell deformation resistance. 6 Table of contents List of abbreviations ......................................................................................... 12 Chapter 1: Introduction ..................................................................................... 15 1.1 Cilia and ciliopathies ............................................................................... 15 1.1.1 Introduction to cilia ........................................................................... 15 1.1.2 Ciliary structure ................................................................................ 17 1.1.3 Ciliogenesis ...................................................................................... 17 1.1.4 Ciliary compartmentalisation ............................................................ 22 1.1.5 Cilium-dependent signalling ............................................................. 24 1.1.6 Cilia in development ......................................................................... 31 1.1.7 Ciliopathies ....................................................................................... 31 1.2 Cell adhesion and the extracellular matrix .............................................. 42 1.2.1 Cell adhesion ................................................................................... 42 1.2.2 Focal adhesion morphology ............................................................. 44 1.2.3 The extracellular matrix .................................................................... 47 1.3 Meckel-Gruber syndrome ....................................................................... 53 1.3.1 MKS clinical presentation and genetics ............................................ 53 1.3.2 Cell biology of MKS .......................................................................... 48 1.3.3 MKS model organism studies ........................................................... 63 1.3.4 TMEM67 ........................................................................................... 60 1.3.5 TMEM216 ......................................................................................... 73 1.3.6 Interaction between TMEM67 and TMEM216 .................................. 67 1.4 Summary and aims ................................................................................. 67 Chapter 2: Materials and Methods ................................................................... 71 2.1 Cell culture .............................................................................................. 81 2.2 Surface coating with extracellular matrix protein ..................................... 81 2.3 Cell-derived matrix isolation .................................................................... 82 2.4 Antibodies and probes ............................................................................ 83 2.5 Western blotting ...................................................................................... 83 2.6 Immunofluorescence and phalloidin staining .......................................... 84 2.7 Transfection ............................................................................................ 85 2.8 Light microscopy ..................................................................................... 86 2.9 Scanning electron microscopy ................................................................ 86 2.10 Cell spreading analysis ......................................................................... 87 2.11 Cell volume measurement .................................................................... 77 2.12 Adhesion measurement ........................................................................ 77 2.13 Micropipette aspiration .......................................................................... 78 2.14 Micropipette data analysis .................................................................... 79 2.15 Actin co-sedimentation .......................................................................... 90 7 2.16 Total mRNA isolation ............................................................................ 92 2.17 Differential expression analysis and gene set enrichment analysis ...... 92 2.18 Focal adhesion isolation ....................................................................... 92 2.19 Tandem mass tag mass spectrometry .................................................. 93 2.20 Statistical analysis................................................................................
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