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Canonical Wnt Signalling in Xenopus Simon Wilfred Fellgett

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Canonical Wnt Signalling in Xenopus Simon Wilfred Fellgett The effects of Sulf1 on canonical and non- canonical Wnt signalling in Xenopus Simon Wilfred Fellgett Thesis submitted for the degree of Doctor of Philosophy The University of York Department of Biology September 2013 Abstract Heparan sulphate proteoglycans are large macromolecules expressed on the cell surface. They are an important part of the extracellular matrix and regulate multiple cell signalling pathways. Sulf1 is an extracellular sulfatase that specifically removes 6-O linked sulphate groups from heparan sulphate chains. The activity of Sulf1 alters the ability of heparan sulphate chains to regulate FGF, BMP, hedgehog and Wnt signalling pathways. The original work that identified Sulf1 (Dhoot et al., 2001), demonstrated that Sulf1 enhanced the ability of Wnt1 to activate canonical Wnt signalling. This thesis uses Xenopus to investigate the effects of Sulf1 on canonical and non-canonical Wnt signalling in the early embryo. Sulf1 has ligand specific effects on different Wnt ligands, inhibiting the ability of Wnt8a, but not Wnt3a, to activate canonical Wnt signalling. In addition Sulf1 potentiates the ability of Wnt4 to activate non- canonical Wnt signalling and Wnt11b to activate both canonical and non- canonical Wnt signalling. Confocal analysis of animal caps expressing fluorescently tagged Wnt ligands shows that Sulf1 can enhance the range of diffusion of both Wnt8a and Wnt11b. The ability of Sulf1 to regulate Wnt ligand diffusion may explain some of the differential effects of Sulf1 on Wnt signalling. The results described in this thesis are discussed in terms of Sulf1 regulating Wnt morphogen gradients during development. The differential effects of Sulf1 on canonical and non-canonical Wnt signalling described here requires more than the existing ‘catch and present’ model (Ai et al., 2003). A new model is presented here. 2 Table of contents Abstract ................................................................................................................. 2 Table of contents ................................................................................................... 3 Acknowledgments ............................................................................................... 15 Author’s declaration ............................................................................................. 17 1.0 Introduction.................................................................................................. 18 1.1.0 Determination of cell fate by morphogens ................................................... 19 1.2.0 Identification the Wg pathway in Drosophila ................................................ 20 1.2.1 The Wg signalling pathway ......................................................................... 22 1.2.2 The Drosophila planar cell polarity pathway ................................................ 26 1.3.0 The vertebrate Wnts ................................................................................... 28 1.3.1 Wnt/Wg synthesis and secretion ................................................................. 30 1.3.2 The canonical Wnt receptors ...................................................................... 31 1.3.3 The canonical Wnt signalling pathway ........................................................ 33 In the absence of Wnt ...................................................................................... 33 In the presence of Wnt ..................................................................................... 34 1.4.0 Establishing the organiser domain .............................................................. 35 1.4.1 Cell behaviour during gastrulation ............................................................... 37 1.4.2 Regulating vertebrate gastrulation .............................................................. 38 1.5.0 The role of non-canonical Wnt signalling during gastrulation ....................... 39 1.5.1 The PCP pathway regulates cell behaviour during gastrulation ................... 40 1.5.2 The Wnt/calcium pathway ........................................................................... 42 1.6.0 Cross regulation of the canonical and non-canonical Wnt signalling pathways ............................................................................................................................ 44 1.6.1 Activating the canonical and non-canonical Wnt signalling cascades .......... 46 1.6.2 Intracellular trafficking of Wnt receptor complexes ...................................... 48 1.7.0 Heparan sulphate proteoglycans ................................................................ 49 1.7.1 Membrane bound HSPGs ........................................................................... 50 Syndecans ....................................................................................................... 50 3 Glypicans ......................................................................................................... 50 Perlecans ......................................................................................................... 51 1.7.2 HSPG synthesis .......................................................................................... 52 Chain initiation.................................................................................................. 52 Chain polymerisation ........................................................................................ 53 Chain modifications .......................................................................................... 53 1.7.3 HSPGs regulate a variety of developmental signalling pathways ................ 54 1.7.4 HSPGs require sulphate modifications to activate cell signalling ................. 56 1.8.0 Post synthetic modification of HSPGs by the extracellular sulfatases Sulf1 and 2 ................................................................................................................... 58 Sulf1 ................................................................................................................. 58 Sulf 2 ................................................................................................................ 59 1.8.1 Sulf1 has a regulatory function during development .................................... 60 1.8.2 Sulf1 modulates multiple cell signalling pathways ....................................... 61 FGF signalling .................................................................................................. 61 BMP signalling ................................................................................................. 62 Wnt signalling ................................................................................................... 62 1.9.0 Aims of this study ........................................................................................ 65 2.0 Materials and Methods ........................................................................... 66 2.1 Materials and solutions ............................................................................ 67 2.1.1 Summary of materials ................................................................................. 67 2.1.2 Summary of solutions ................................................................................. 70 2.1.3 Summary of antibodies ............................................................................... 74 In situ hybridisation .......................................................................................... 74 Western blot ..................................................................................................... 74 2.2 Embryological methods ........................................................................... 74 2.2.1 Xenopus laevis in vitro fertilisation and culture ............................................ 74 2.2.2 Xenopus tropicalis in vitro fertilisation and culture ....................................... 75 2.2.3 Microinjection .............................................................................................. 75 2.2.4 Animal cap assays ...................................................................................... 76 Convergent extension assays .......................................................................... 76 4 Western blot ..................................................................................................... 76 Confocal microscopy ........................................................................................ 76 2.2.5 In situ hybridisation ..................................................................................... 77 2.2.6 Photography ............................................................................................... 78 2.3 Molecular biology methods ...................................................................... 78 2.3.1 Transformation ............................................................................................ 78 2.3.2 Colony PCR ................................................................................................ 78 2.3.3 Agarose gel electrophoresis ........................................................................ 79 2.3.4 DNA minipreps ............................................................................................ 79 2.3.5 Quantification of DNA and RNA .................................................................. 79 2.3.6 Sequencing ................................................................................................. 80 2.3.7 Linearizing plasmid DNA
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