Please use this identifier to cite or link to this item: http://hdl.handle.net/2445/48407
Title: The contribution of LMO4 to neural development: generatin neuronal subtypes in the dorsal spinal cord and controlling EMT in neural crest cells and Neuroblastoma = La contribución de LMO4 al desarrollo neural: la generación de subtipos neuronales de la médula dorsal espinal y el control de la EMT en las células de la cresta neural y de Neuroblastoma
Author: Ferronha, Tiago Guimaràes
Director: Marti Gorostiza, Elisa
Le Dréau, Gwenvael
Romero, Rafael, 1967-
Keywords: Sistema nerviós
Nervous system
Cresta neural
Neural crest
Neuroblastoma
Interneurona
Interneuron
LMO4 (Genètica)
LMO4 (Genetics)
Issue Date: 16-Jul-2013
Publisher: Universitat de Barcelona
Abstract: [spa]La formación del sistema nervioso central requiere la generación de una gran diversidad de neuronas, y la identificación de las señales moleculares que regulan este proceso es por lo tanto crucial. En esta tesis, me he centrado primero en estudiar la función de LMO4 durante la neurogénesis en la médula espinal dorsal. Mediante las electroporación in ovo, en embriones de pollo, como una metodología para modular la actividad LMO4 in vivo, se demostró que LMO4 era prescindible para el mantenimiento de los patrones de progenitores, pero que se requiere para la correcta generación de subtipos concretos de interneuronas dorsales (dI1/3/5). Por otra parte, se demostró que la actividad LMO4 es esencial para la promoción de estas identidades mediante la actividad BMP canónica, y proponemos que LMO4 y Smad1 / 5 forman parte de los complejos de proteínas que impulsan el programa genético de especificación de dI1/3/5. En la segunda parte de la tesis, he estudiado el sistema nervioso periférico, así como tumores que surgen de él. El neuroblastoma es un tumor embrionario derivado de células de la cresta neural. Aprovechando un nuevo marcador desarrollo para el linaje de cresta neural y en base a la hipótesis de que los mecanismos moleculares que median la delaminación de la cresta neural también están involucrados en la propagación del neuroblastoma, identificamos varios genes comunes en el desarrollo de la cresta neural y el neuroblastoma. Una búsqueda posterior de los ortólogos humanos del NBGS (genes expresados en neuroblastoma) observamos que LMO4 se expresa en ambos tipos de células analizadas. Experimentos funcionales en estos dos sistemas modelo revelaron que se requiere la actividad LMO4 durante la invasión de células del neuroblastoma y durante la delaminación de la cresta neural. Además, identificamos LMO4 como un cofactor esencial de Snail2, en la represión de la expresión de cadherina, y por tanto en la transición epitelio mesenchyma de la cresta neural y de las células de neuroblastoma. En conjunto, nuestros resultados sugieren que la asociación de altos niveles de LMO4 con neuroblastomas agresivos depende de la regulación de cadherina y, por tanto, de la invasividad tumoral.
[eng]The formation of the central nervous system (CNS) requires the generation of a remarkable diversity of neurons, which must be produced in adequate amounts in the location and timing during development. Studies on the development of the spinal cord, the caudal and simpler anatomically vertebrate CNS, have shown that the neuronal diversity is progressively acquired through the processes of cell type specification. In amniotes, patterning of the neural tube along the dorsal-ventral axis generate 11 distinct domains of neural progenitors. Thus, the developing spinal cord, may be subdivided into 6 dorsal domains of progenitors (dP1-6, from dorsal to ventral) and a ventral part consisting of 5 domains (p3, pMN, p2-0, of ventral to dorsal). Dorsal and ventral domains of progenitors generate classes spinal neurons involved in sensory and motor circuits, respectively. Thus, accurate identification of each of the molecules that regulate this process is crucial. First, in this study, we focus on the function of LMO4 during neurogenesis in the development of the dorsal spinal cord. Using electroporation in ovo, in chicken embryos, as a method for modulating the activity of LMO4 in vivo, we demonstrated that LMO4 is dispensable for maintaining patterns progenitor cells, but is necessary for proper generation of discrete classes of interneurons ie , dI1/3/5. Further we provided evidence that LMO4 activity is essential for the promotion of these identities by the canonical BMP activity and suggest that LMO4 and SMAD1 / 5 contribute to the multi-protein complexes that regulate the genetic program for the specification of interneurons dI1 / 3/5. In the second part of this thesis, we study the peripheral nervous system, PNS, and one type of cancer that is derived from the PNS. Neuroblastoma (NB) is a neurological tumor that arises from neural crest cells (NC) and is the most common extracranial tumor in children. NB represents a very heterogeneous group of tumors in terms of biological, genetic and morphological characteristics. Clinically, these tumors can develop differently, since spontaneous remission differentiation or apoptosis (NC behavior resembling normal) to aggressive metastatic disease with low rates of overall survival. The neuroectodermal origin of NB suggests that these tumors can spread from its primary site using mechanisms similar to those involved in the delamination and dispersion of embryonic neural crest cells, and genes involved in cell migration of neural crest cells may also be involved in the acquisition of the phenotype of invasive NB. We developed marker for neural crest lineage and taking the hypothesis that the molecular mechanisms that mediate the neural crest delamination may also be involved in the spread of neuroblastoma, we were able to identify genes that are expressed in the neural crest development and formation of neuroblastoma. A subsequent search in the NBGS (neuroblastoma gene server) for the human orthologous of genes differentially expressed in neural crest chicken embryo, retrieved LMO4 which was expressed in both cell types tested. Functional experiments in these two systems, revealed that the activity LMO4 is required for delamination of the neural crest and for neuroblastoma cell invasion. Moreover, LMO4 identified as an essential cofactor in the cadherin repression mediated Snail2 and epithelial to mesenchymal transition from neural crest cells and neuroblastoma. Together, our results suggest that the association of high levels of LMO4 with aggressive neuroblastomas, depends on the regulation of cadherin expression by LMO4 and therefore tumor invasiveness.
URI: http://hdl.handle.net/2445/48407
Appears in Collections:Tesis Doctorals - Departament - Genètica

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