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Differentiation of Spinal Cord Neural Precursors and Hippocampal Neurons: a Role for Wnt and Β- Catenin”

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Differentiation of Spinal Cord Neural Precursors and Hippocampal Neurons: a Role for Wnt and Β- Catenin” Departament de Ciències Mèdiques Bàsiques Differentiation of spinal cord neural precursors and hippocampal neurons: a role for Wnt and β-catenin Monica Delia David Doctoral Thesis Judit Herreros Danés Supervisor Judit Herreros Danés, doctor in Biological Sciences and Ramón y Cajal researcher of the Departament de Ciències Mèdiques Bàsiques of Universitat de Lleida, as supervisor of this thesis Hereby states that, Monica Delia David, who majored in Medicine at the Medicine and Pharmacy University Cluj-Napoca, Romania, has performed under mi direction and supervision, and within the Cell Signalling and Apoptosis Group of the Departament de Ciències Mèdiques Bàsiques, the experimental work entitled “Differentiation of spinal cord neural precursors and hippocampal neurons: a role for Wnt and β- catenin”. The work accomplishes the adequate conditions in order to be defended in front of the corresponding Thesis Committee and, if it is case, to obtain the Doctor degree from Universitat de Lleida. Signed: Dr. Judit Herreros Danés, PhD Lleida, January 2009 Quiero expresar mi sincera gratitud a todos aquellos que me han ayudado y que han soportado mi “mala leche” durante el tiempo que ha durado este trabajo. En particular quiero agradecer a: Mi directora de tesis Judit Herreros, por los consejos y la ayuda prestada para llevar a cabo este trabajo. Siento comunicarte que sigo odiando a las ratas y a los ratones. Carles, por tu ayuda y por ser tan paciente. Joan Comella, por vincularme a este laboratorio. Instituto Carlos III y UdL por el soporte económico que ha hecho posible el trabajo. Andree, por tu ayuda en el laboratorio y las divertidas discusiones en la sala del café. Y no tanto por todas las manías en el trabajo que he heredado de tí. Marta, Dani, Carme Gallego y Martí Aldea por los consejos y comentarios tan útiles para mi trabajo. Isu, Rosa y Roser por toda la ayuda y los consejos que me han dado. Roser, por todo el trabajo que has hecho por mí con los animales y que me ha hecho la vida mucho más fácil. Núria B. por tu ayuda en los arreglos de mi tesis y la información sobre los procedimientos a seguir. Sin ellos continuaría “viviendo tranquila y feliz en mi mundo” (como siempre me dices) pero no habría pasado la comisión de doctorado. Maya por no conformarte con lo que hay y siempre querer algo mejor. Jisheng por las clases de chino aunque no aprendí nada, ni siquiera pronunciar bien tu nombre. Pero tranquilo, tú tampoco pronuncias bien el mío. Ana V. y David (los malos) por criticar (constructivamente por supuesto) como hablo un idioma que solo yo puedo entender... aunque estoy convencida de que hablo castellano. Suerte que existe Dolors (la buena), gracias por defenderme. Arindam, Núria E., Annabel, Anna, Esteban, Xavi, Mario, Valdi por vuestra amistad y la atmósfera que creáis en la sala de café. Y también a todos que formaron parte de este grupo Rosa Soler, Miquel, Mary, Yolanda, Carme, Raffaella, Gordana, Sonia. Las alegres chicas de Nefro: Anna C., Sara, Petya, Montse y Millica. Y Eva (Dra. Parisi como pretendes que te llame) por toda tu sabiduría y no recuerdo que más me has dicho que ponga. Gemma por tu compañía en verano y todas las fotos divertidas que has hecho en el laboratorio. Multumesc familiei mele pentru tot sprijinul si ajutorul acordat. Index ABBREVIATIONS ........................................................................................ III ABSTRACT .................................................................................................VII IINTRODUCTIONNTRODUCTION........................................................................................- 1 - 1. Neurogenesis ................................................................................................................................3 1.1. The role of morphogens in neurogenesis.............................................................................6 1.2. Establishment of the neuronal morphology .........................................................................8 2. Wnt signalling............................................................................................................................11 2.1. Wnts receptors ...................................................................................................................14 2.2. Extracellular modulators of Wnt signalling.......................................................................14 2.3. Wnt pathways ....................................................................................................................16 2.3.1. Canonical Wnt/β-catenin pathway ................................................................................16 2.3.2. Non-canonical pathways...............................................................................................17 3. Growth factors...........................................................................................................................18 3.1. Neurotrophins ....................................................................................................................19 3.1.1. Trk receptors .................................................................................................................19 3.1.2. p75NTR receptor ..........................................................................................................20 3.1.3. Neurotrophin receptor expression.................................................................................21 3.1.4. Neurotrophin signalling ................................................................................................21 3.1.5. Roles of neurotrophins in the nervous system ..............................................................22 3.2. Hepatocyte growth factor (HGF).......................................................................................24 3.2.1. HGF receptor ................................................................................................................25 3.2.2. HGF roles......................................................................................................................27 3.3. Epidermal growth factor ....................................................................................................27 4. β- catenin....................................................................................................................................29 4.1. The cadherin-catenin complex...........................................................................................30 4.2. Regulation of β-catenin signalling by the Wnt pathway....................................................32 4.3. Regulation of β-catenin function by tyrosine phosphorylation..........................................32 OOBJECTIVESBJECTIVES .............................................................................................. 37 MATERIALS AND METHODS..................................................................... 41 1. Materials ....................................................................................................................................43 2. Cell culture.................................................................................................................................43 2.1. Cell lines and culture conditions........................................................................................43 2.2. Primary culture ..................................................................................................................44 2.2.1. Isolation and culture of mouse SCNPs..........................................................................44 2.2.2. Isolation and culture of rat hippocampal neurons ........................................................45 3. Cell transfection.........................................................................................................................46 3.1. Polyethilenimine cell transfection......................................................................................46 3.2. LipofectamineTM2000 cell transfection..............................................................................46 3.3. Nucleofection of SCNP cells. ............................................................................................46 4. Lentiviral-driven shRNA expression .......................................................................................47 4.1. Lentiviral constructs ..........................................................................................................47 4.2. Lentiviral production .........................................................................................................47 I Index 4.3. Cell transduction ............................................................................................................... 48 5. Cellular lysis and Western Blot assay ..................................................................................... 49 5.1. Cell lysis............................................................................................................................ 49 5.2. Western blot ...................................................................................................................... 49 6. Immunoprecipitations .............................................................................................................. 49 6.1. NP40 and RIPA solubilization .......................................................................................... 50 6.2. Immunoprecipitation ........................................................................................................
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