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Analysis of Reelin Function in Brain Development and in Adult Neurogenesis

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Analysis of Reelin function in brain development and in adult neurogenesis Análisis de la función de Reelina en el desarrollo del cerebro y la neurogénesis adulta Alba del Valle Vílchez Acosta ADVERTIMENT. La consulta d’aquesta tesi queda condicionada a l’acceptació de les següents condicions d'ús: La difusió d’aquesta tesi per mitjà del servei TDX (www.tdx.cat) i a través del Dipòsit Digital de la UB (diposit.ub.edu) ha estat autoritzada pels titulars dels drets de propietat intelꞏlectual únicament per a usos privats emmarcats en activitats d’investigació i docència. No s’autoritza la seva reproducció amb finalitats de lucre ni la seva difusió i posada a disposició des d’un lloc aliè al servei TDX ni al Dipòsit Digital de la UB. No s’autoritza la presentació del seu contingut en una finestra o marc aliè a TDX o al Dipòsit Digital de la UB (framing). Aquesta reserva de drets afecta tant al resum de presentació de la tesi com als seus continguts. En la utilització o cita de parts de la tesi és obligat indicar el nom de la persona autora. ADVERTENCIA. La consulta de esta tesis queda condicionada a la aceptación de las siguientes condiciones de uso: La difusión de esta tesis por medio del servicio TDR (www.tdx.cat) y a través del Repositorio Digital de la UB (diposit.ub.edu) ha sido autorizada por los titulares de los derechos de propiedad intelectual únicamente para usos privados enmarcados en actividades de investigación y docencia. No se autoriza su reproducción con finalidades de lucro ni su difusión y puesta a disposición desde un sitio ajeno al servicio TDR o al Repositorio Digital de la UB. No se autoriza la presentación de su contenido en una ventana o marco ajeno a TDR o al Repositorio Digital de la UB (framing). Esta reserva de derechos afecta tanto al resumen de presentación de la tesis como a sus contenidos. En la utilización o cita de partes de la tesis es obligado indicar el nombre de la persona autora. WARNING. On having consulted this thesis you’re accepting the following use conditions: Spreading this thesis by the TDX (www.tdx.cat) service and by the UB Digital Repository (diposit.ub.edu) has been authorized by the titular of the intellectual property rights only for private uses placed in investigation and teaching activities. Reproduction with lucrative aims is not authorized nor its spreading and availability from a site foreign to the TDX service or to the UB Digital Repository. Introducing its content in a window or frame foreign to the TDX service or to the UB Digital Repository is not authorized (framing). Those rights affect to the presentation summary of the thesis as well as to its contents. In the using or citation of parts of the thesis it’s obliged to indicate the name of the author. UNIVERSITAT DE BARCELONA FACULTAT DE BIOLOGIA DEPARTAMENTO DE BIOLOGIA CEL·LULAR, FISIOLOGIA I IMMUNOLOGIA PARC CIENTÍFIC DE BARCELONA Analysis of Reelin function in brain development and in adult neurogenesis Alba del Valle Vílchez Acosta Barcelona, 2019 Programa Doctorado Biomedicina UNIVERSITAT DE BARCELONA FACULTAT DE BIOLOGIA DEPARTAMENTO DE BIOLOGIA CEL·LULAR, FISIOLOGIA I IMMUNOLOGIA PARC CIENTÍFIC DE BARCELONA Analysis of Reelin function in brain development and in adult neurogenesis Análisis de la función de Reelina en el desarrollo del cerebro y la neurogénesis adulta Programa Doctorado Biomedicina Memoria presentada por Alba del Valle Vílchez Acosta, licenciada en Biotecnología, para optar al grado de Doctora por la Universitat de Barcelona. Los Estudios de tercer ciclo se han enmarcado en el programa de Doctorado en Biomedicina de la Universitat de Barcelona. El proyecto de Tesis Doctoral está inscrito al Departamento de Biologia Cel·lular, Fisiologia i Immunologia de la Facultat de Biologia de la Universitat de Barcelona. El trabajo experimental y la redacción de la memoria que se presentan han estado dirigidos por el Dr. Eduardo Soriano García y la Dra. Yasmina Manso Sanz. Barcelona, septiembre de 2019 Dr. Eduardo Soriano García Dra. Yasmina Manso Sanz Doctoranda Alba del Valle Vílchez Acosta A mi abuela Valle, A mis padres y a Jorge. Je suis de ceux qui pensent que la science est d’une grande beauté. Un scientifique Caminante, son tus huellas dans son laboratoire est non seulement un el camino y nada más; technicien : il est aussi un enfant placé Caminante, no hay camino, devant des phénomènes naturels qui se hace camino al andar. l’impressionnent comme des contes de fées. Maria Salomea Skłodowska-Curie Antonio Machado (Sevilla-Colliure) (Varsovia-Passy) ACKNOWLEDGMENT Este capítulo de mi vida está a punto de cerrarse y me gustaría dedicar unas breves palabras de agradecimiento a todas aquellas personas que han sido partícipes y han hecho posible que esta tesis llegue al final de su recorrido. En primer lugar me gustaría dar las gracias al Dr. Eduardo Soriano, gracias por abrirme las puertas del laboratorio, por confiar en mí y por darme la oportunidad de poder realizar esta tesis. A la Dra. Yasmina Manso, gracias por enseñarme tanto, gracias por tus consejos y gracias por haberme guiado durante todo este tiempo. Muchas gracias a los dos por haber dirigido esta tesis. A los compañeros del laboratorio, GRACIAS a todos, a los que siguen y a los que ya se fueron. En especial me gustaría dar las gracias a Ash, porque sin ti nos volveríamos locos. A Núria, por dejarnos de herencia tú trabajo. A Sere y a Dani (ciao ragazzi!), por vuestra ayuda y vuestra alegría. También me gustaría dar las gracias a todos los estudiantes que han pasado por el laboratorio, Laia, Berta, Lorena, muchísimas gracias por vuestro trabajo. Berta, esto se merece unas buenas croquetas!. También me gustaría agradecer a todo el personal de plataformas técnicas y estabularios sin los cuales hubiera sido imposible realizar todo este trabajo. En especial a las chicas de microscopía del Clínic (María, Elisenda y Anna) y del Parc. También al personal de los estabularios, David, Laia. Muchísmas gracias por todo. Gracias también al Dr. Víctor Borrell por permitirme realizar una estancia en su laboratorio. Gracias Adri, Ana, Salma, Lucía, Cristina… por haberme acogido y ayudado durante mi estancia. Gracias también a Michael, quién diría que el destino nos volvería a juntar! Grazie di tutto! La lista de todos los que me habéis ayudado durante estos cuatro años es muy larga, a todos GRACIAS. Pero para llegar hasta aquí el camino fue largo y me gustaría agradecer a todas las personas que me han ayudado a recorrerlo. En primer lugar a Matilde, a Luisa, al Dr. Juanjo, porque la vida es como una carrera de obstáculos pero uno nunca se rinde hasta que no cruza la meta. Des personnes de Paris… Angelique, Danica, Carola, Human, Joan… merci pour tout. Gracias a mis Biotecs, por compartir conmigo 5 años tan increíbles. A mis pilimilitrini, Angie, Clara, por ser siempre, porque siempre es un hasta luego. Parras, Paula, porque nuestros caminos se sigan cruzando. A los planarios, por ser mi alegría en Barcelona. Por hacerme sentir un poquito más en casa. Gracias Giulia, Carles, Liska, Sara, Arantxa, Aleix… Gracias a ti Jordi, y a tu familia, por cuidarme tanto. Angeleta, por enseñarme la cuina catalana. A ti Jordi, gracias por traerme hasta aquí y por descubrir conmigo tantas cosas. Gracias por confiar siempre en mí. Gracias a todos los que de una forma u otra han hecho que Barcelona fuese mi segunda casa. Gracias Cone, por ayudarme siempre. Gracias Elena, por traer un poco de sur al norte. Gracias Ana y Nathan, por enseñarme las buenas sorpresas que te da la vida. Gracias a mis Andaluzas, por levantarme el ánimo cuando más lo necesitaba. Gracias Marta, por estar siempre dispuesta a todo. Gracias a Andreu, por compartir conmigo el mejor congreso. Gracias a ti Artur, Arturitooo, porque siempre nos quedará Bruno Mars... Y gracias a todos los que habéis compartido conmigo tantos momentos durante estos años. A mis amigos de siempre, los de Pinoloko (sí tenía que aparecer), porque de allí venimos y mira dónde estamos. Fernan, Javi, Sergio, gracias por ser y estar, por hacerme querer volver siempre, por recordarme quién soy. Gracias Sergio, por tener siempre un momento para mí. A los tres, gracias de todo corazón. Si he llegado hasta aquí sin duda ha sido gracias a la PhD family. Gracias Marc, porque gracias a tí uno aprende a relativizar las cosas XD. A ti Cris… tengo tantas cosas que agradecerte que podría escribir otra tesis. Ha sido una suerte tenerte de compañera de tesis. Gràcies Toni, per haver sigut el meu company en moltíssims aspectes. Gràcies perquè sense tu, ara no seria qui soc. Especialment, gràcies per escoltar les meves reflexions infumables sobre el món de la Reelina, sense els teus consells i la teva paciència aquesta tesi no seria el que és. Por último, quiero dar las gracias a mi familia. Pepa, Sole, tita Antonia, abuela, Gabi, Sandra, Reyes, Cristóbal, María… Gracias porque sin vosotros no sería quien soy. Gracias Papá, Mamá y Jorge por todo. Gracias Jorge por ser el mejor hermano del mundo. Crecer a tu lado ha sido la mejor experiencia de mi vida. Gracias Papá, por ser como dicen los Carapapas mi primer amor. Gracias Mamá, por enseñarme lo que significan las alas, y ayudarme a volar siempre. GRACIAS por ser mi hogar, y por vuestro apoyo incondicional, esta tesis es de los cuatro. A tots, gràcies. A todos, gracias. ABSTRACT Reelin is a large extracellular matrix glycoprotein with a crucial role both during brain development, where it is key for neuronal migration and for the formation of the layered structure of cerebral cortex and cerebellum, and in the adulthood, where it is involved in adult synaptic plasticity, including neurogenesis in the dentate gyrus and dendritogenesis amongst other processes.
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    The GeneCards Suite: From Gene Data UNIT 1.30 Mining to Disease Genome Sequence Analyses Gil Stelzer,1,5 Naomi Rosen,1,5 Inbar Plaschkes,1,2 Shahar Zimmerman,1 Michal Twik,1 Simon Fishilevich,1 Tsippi Iny Stein,1 Ron Nudel,1 Iris Lieder,2 Yaron Mazor,2 Sergey Kaplan,2 Dvir Dahary,2,4 David Warshawsky,3 Yaron Guan-Golan,3 Asher Kohn,3 Noa Rappaport,1 Marilyn Safran,1 and Doron Lancet1,6 1Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel 2LifeMap Sciences Ltd., Tel Aviv, Israel 3LifeMap Sciences Inc., Marshfield, Massachusetts 4Toldot Genetics Ltd., Hod Hasharon, Israel 5These authors contributed equally to the paper 6Corresponding author GeneCards, the human gene compendium, enables researchers to effectively navigate and inter-relate the wide universe of human genes, diseases, variants, proteins, cells, and biological pathways. Our recently launched Version 4 has a revamped infrastructure facilitating faster data updates, better-targeted data queries, and friendlier user experience. It also provides a stronger foundation for the GeneCards suite of companion databases and analysis tools. Improved data unification includes gene-disease links via MalaCards and merged biological pathways via PathCards, as well as drug information and proteome expression. VarElect, another suite member, is a phenotype prioritizer for next-generation sequencing, leveraging the GeneCards and MalaCards knowledgebase. It au- tomatically infers direct and indirect scored associations between hundreds or even thousands of variant-containing genes and disease phenotype terms. Var- Elect’s capabilities, either independently or within TGex, our comprehensive variant analysis pipeline, help prepare for the challenge of clinical projects that involve thousands of exome/genome NGS analyses.
  • CRL5-Dependent Regulation of the Small Gtpases ARL4C and ARF6 Controls Hippocampal Morphogenesis

    CRL5-Dependent Regulation of the Small Gtpases ARL4C and ARF6 Controls Hippocampal Morphogenesis

    CRL5-dependent regulation of the small GTPases ARL4C and ARF6 controls hippocampal morphogenesis Jisoo S. Hana,1, Keiko Hinoa,1, Wenzhe Lia, Raenier V. Reyesa, Cesar P. Canalesa,2, Adam M. Miltnera, Yasmin Haddadia, Junqing Sunb, Chao-Yin Chenb, Anna La Torrea, and Sergi Simóa,3 aDepartment of Cell Biology and Human Anatomy, University of California, Davis, CA 95616; and bDepartment of Pharmacology, University of California, Davis, CA 95616 Edited by Mary E. Hatten, Rockefeller University, New York, NY, and approved August 3, 2020 (received for review February 14, 2020) The small GTPase ARL4C participates in the regulation of cell migra- Importantly, CRL5 substrate adaptors are dynamically regulated tion, cytoskeletal rearrangements, and vesicular trafficking in epithe- during development, directing CRL5 activity to specific substrates lial cells. The ARL4C signaling cascade starts by the recruitment of the at different times and areas in the CNS (19). In the neocortex, ARF–GEF cytohesins to the plasma membrane, which, in turn, bind CRL5 opposes projection neuron migration by down-regulating and activate the small GTPase ARF6. However, the role of ARL4C– the Reelin/DAB1 signaling pathway as migrating projection neu- cytohesin–ARF6 signaling during hippocampal development remains rons reach the top of the cortical plate (18, 20, 21). In the CNS, elusive. Here, we report that the E3 ubiquitin ligase Cullin 5/RBX2 Reelin/DAB1 signaling participates in several developmental (CRL5) controls the stability of ARL4C and its signaling effectors to processes, including neuron migration, dendritogenesis, axo- regulate hippocampal morphogenesis. Both RBX2 knockout and genesis, and synaptogenesis (22–24). Moreover, CRL5 also con- Cullin 5 knockdown cause hippocampal pyramidal neuron mislocali- trols levels of the tyrosine kinase FYN, which exerts important zation and development of multiple apical dendrites.