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The Role of GDF5 in the Developing Vertebrate Nervous System

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The Role of GDF5 in the Developing Vertebrate Nervous System The role of GDF5 in the developing vertebrate nervous system A thesis submitted to Cardiff University for the degree of PhD 2015 Christopher William Laurie Cardiff School of Biosciences Cardiff University Mae hwn yn ymroddedig I fy mhrydferth rhyfeddol, hebddi fyddai heb lwyddo. Dwi’n toddi, rwt ti wedi gwneud fi mor hapus. Declaration This work has not been submitted in substance for any other degree or award at this or any other university or place of learning, nor is being submitted concurrently in candidature for any degree or other award. Signed ………………………………………… (candidate) Date ………………………… STATEMENT 1 This thesis is being submitted in partial fulfillment of the requirements for the degree of …………………………(insert MCh, MD, MPhil, PhD etc, as appropriate) Signed ………………………………………… (candidate) Date ………………………… STATEMENT 2 This thesis is the result of my own independent work/investigation, except where otherwise stated. Other sources are acknowledged by explicit references. The views expressed are my own. Signed ………………………………………… (candidate) Date ………………………… STATEMENT 3 I hereby give consent for my thesis, if accepted, to be available online in the University’s Open Access repository and for inter-library loan, and for the title and summary to be made available to outside organisations. Signed ………………………………………… (candidate) Date ………………………… STATEMENT 4: PREVIOUSLY APPROVED BAR ON ACCESS I hereby give consent for my thesis, if accepted, to be available online in the University’s Open Access repository and for inter-library loans after expiry of a bar on access previously approved by the Academic Standards & Quality Committee. Signed ………………………………………… (candidate) Date ………………………… i Acknowledgements I would first and foremost like to thank Dr Sean Wyatt for giving me the opportunity to pursue my PhD. Thank you for being an amazing supervisor and friend by providing limitless advice and support during my time in the lab. I have been extremely lucky to have a supervisor who was so engaging and who appeared to have limitless patience and put up so courteously with my stupid questions! I do not think any PhD student could ask for a better supervisor. Thank you for everything. Thank you to Prof. Alun Davies for enabling me to tackle such an interesting research project and all the good advice along the way. Special thanks to Clara Jureky and Dr Laura Howard for making my time in lab so enjoyable and putting up with me in such a gracious manner! Thank you to Dr Catarina Osório for all her support, teaching of techniques, and general expertise as I began to embark on this research project. To all the other members of the Wyatt and Davies lab, both past and present, for you for creating such an excellent working environment and being such good friends. Thanks to all my friends, those from Cardiff, those from home and those who have moved on to new and exciting challenges in new locations. I would like to thank all my family for making it possible to complete my PhD, especially my Dad whose constant support made this all possible. Finally, to the most amazing wonderful friend any man could have. Your constant presence, love, friendship and unwavering support made this all possible. You were always happy to see me when I got home at stupid times of night, no matter how grumpy I was. I owe you more than I could ever repay. So this thesis is dedicated to you, the most amazing and wonderful dog in the world, Woody Laurie. And I should probably thank my wife, Becky Laurie. ii Abstract This thesis aimed to examine the roles of growth differentiation factor 5 (GDF5), a secreted member of the TGF-β superfamily of ligands with a well characterised role in limb morphogenesis, in the developing hippocampus and sympathetic nervous system. Previous studies have demonstrated that GDF5 promotes the growth and elaboration of dendrites from developing mouse hippocampal neurons in vitro and in vivo. As a first step to investigating whether GDF5 plays additional roles in the development of the mouse hippocampus, brains of P10 and adult Gdf5+/+, Gdf5+/bp and Gdf5bp/bp mice were analysed by anatomical MRI. The gross morphology and total volume of hippocampi were not significantly different between the three genotypes at either age, making it unlikely that GDF5 plays a significant role in modulating other aspects of hippocampal development in addition to promoting the growth and elaboration of dendrites. For this reason, no further time was spent on investigating whether GDF5 plays novel roles in regulating hippocampal development. Developing sympathetic neurons of the mouse superior cervical ganglion (SCG) require nerve growth factor (NGF) to promote their survival and target field innervation in vivo. Data in this thesis has revealed that GDF5 modulates NGF promoted survival and enhances NGF promoted process outgrowth in cultures of P0 SCG neurons. In addition, GDF5 promotes process outgrowth and branching from cultured perinatal SCG neurons in the absence of NGF. P10 Gdf5bp/bp mice, that lack functional GDF5 expression, display a marked deficit in sympathetic innervation of the iris, but not the submandibular gland, compared to P10 Gdf5+/+ mice. Whole-mount analysis of sympathetic innervation in P10 Gdf5bp/bp and Gdf5+/+ mice has revealed that GDF5 is required for correct innervation of the trachea and heart, but not the pineal gland. Further in vitro and in vivo investigations have suggested that the neurotrophic effects of GDF5 on developing SCG neurons are mediated by a receptor complex that includes the type 1 receptor, BMPR1A. These findings highlight a role for GDF5 in promoting the sympathetic innervation of selective target fields in vivo. iii Abbreviations Abbreviations Ab- Antibody Ach - Acetylcholine ACVR2 – Activin type 2 receptor ADAM - A disintegrin and metalloprotease domain Akt/PKB- Ak transforming/protein kinase B AP – Anterior-posterior axis APs- Apical progenitors AP-1- Activator protein 1 Apaf - apoptotic protease-activating factor APC - Adenomatous polyposis coli aPKC - atypical protein kinase C ADP - Adenosine diphosphate AIF - Apoptosis Inducing Factor APRIL- A proliferation-inducing ligand ATP- adenosine triphosphate ANS - Autonomic nervous system ARTN - Artemin BABB- 1 part benzyl alcohol: 2 parts benzyl benzoate Bad - BCL2-Associated Agonist Of Cell Death BAFF – B-cell-activator factor BAFFR – BAFF receptor Bak - Bcl2-Antagonist/Killer Bax - Bcl2-Associated X Protein Bcl-2 - B-cell lymphoma-2 BCMA – B-cell maturation antigen BDNF- Brain derived neurotrophic factor BH - Bcl-2 homology Bid – BH3 Interacting Domain Death Agonist Bim - Bcl-2 Interacting Mediator Of Cell Death BMP- Bone morphogenetic protein BMPR –Bone morphogenetic protein Bok - Bcl2-Related Ovarian Killer bp – Base pairs BPs – Basal progentors BSA- Bovine serum albumin °C- degree Celsius C domain – Central Domain Ca2+- Calcium CaCl2- Calcium chloride CAMs- Cell-adhesion molecules iv Abbreviations CaSR- Calcium-sensing receptor CD40- Cluster of differentiation 40 CDKs - Cyclin-dependent kinases cDNA- complementary DNA CDMP – cartilage-derived morphogenetic protein CG- Celiac ganglion cGKI - cGAMP-dependent protein kinase cGMP - Cyclic guanosine monophosphate CGT - Chondrodysplasia Grebe type CHO – Chinese hamster ovary CKI- Casein kinase I Co-Smad - Common mediator Smad CRD - Cysteine-rich domain cm- Centimetre CNP - C-type natriuretic peptide CNS- Central nervous system CNTF- Ciliary neurotrophic factor CO2- Carbon dioxide COS - CV-1 (simian) in Origin, and carrying the SV40 genetic materia CRD- Cysteine-rich domain CT-1- Cardiotrophin-1 Ct value – Cycle threshold value DAG - Diacyl-glycerol DAN – Differential screening-selected gene aberrative in neuroblastoma DAPI – 4’,6-diamidino-2-phenylindole dATP - Deoxyadenosine triphosphate DBH- Dopamine β-hydroxylase DCC - Deleted in Colorectal Carcinomas DcR- Decoy receptor DCX - Doublecortin DD- Death domain DMSO- Dimethyl sulfoxide DMEN – Dulbeccos’s modified Eagle’s mediumDNA-Deoxyribonucleic acid dNTPS- Deoxynucleotides triphosphates Dpp – Decapentaplegic DR3 – Death receptor 3 DREZ - Dorsal root entry zone DRG- Dorsal root ganglia DV – Dorsal-ventral axis DVR – Dpp and vegetal-1 (Vg1)-related E-cadherin – Epithelial cadherin EDA - Ectodysplasin A v Abbreviations E- Embryonic day 1 F-actin - Actin filaments EMT- Epithelial to mesenchymal transition Endothelin-3- End3 ENS - Enteric nervous system ER – Endoplasmic reticulum ERK- Ras/extracellular signal regulated kinase FADD- FAS-associated death domain FAK - Focal Adhesion Kinase FasL – Fas ligand FGF – Fibroblast growth factor FGFR - FGF receptor FOX – Forkhead box FRET- Fluorescence resonance energy transfer FRS2- Fibroblast receptor substrate-2 Fwd – Forward g – Gram G-actin -Globular actin monomers GAB1 - Grb2-associated-binding protein 1 GABA - Gamma-aminobutyric acid GAPDH- Glyceraldehyde 3-phosphate dehydrogenase GDNF- Glial cell derived neurotrophic factor GDP - Guanosine diphosphate GC base pairing – Guanine and Cytosine base pairing GDF – Growth differentiation factor Gdf5bp-J Growth differentiation factor 5, brachypodism-Jackson GFP- Green fluorescent protein GITR- Glucocorticoid-induced tumour necrosis factor-related protein GITRL- Glucocorticoid-induced tumour necrosis factor-related protein ligand GFAP- Glial fibrillary acidic protein GFL – GDNF family ligands GFR – GDNF family receptors GTP - Guanosine triphosphate GPI – Glycosylphosphatidylinositol Grb2 - Growth factor receptor-bound protein 2 GS region - Glycine-serine rich sequence h- Hour H2O2- Hydrogen peroxide
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