Análisis de la función del ligando Wnt5a sobre la diferenciación y desarrollo de nuevas neuronas generadas a partir de progenitores hipocampales adultos
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2017
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es
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Universidad Andrés Bello
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Resumen
La neurogénesis es el proceso de generación de nuevas neuronas en el cerebro adulto. Este
proceso toma lugar en la zona sub granular (SGZ) en el giro dentado (DG) del hipocampo y
en la zona sub ventricular (SVZ) en la pared de los ventrículos laterales. Las células madres
neuronales también llamados progenitores hipocampales adultos (AHPs) están presentes en la
SGZ proliferan y dan paso a neuronas granulares. Éstas células migran a través de la capa de
células granulares (GCL), extendiendo sus dendritas hacia la capa molecular (ML)
integrándose al circuito hipocampal contribuyendo al aprendizaje y la memoria dependiente
del hipocampo. Los AHPs pueden ser aislados del cerebro adulto y ser estudiadas in vitro.
Entre varios mecanismos que modulan la neurogénesis, poco se sabe sobre el rol específico
que tienen las vías de señalización Wnt no canónicas. Como la vía wnt no canónica participa
en el desarrollo morfológico y la diferenciación de las neuronas en las etapas embrionarias
nosotros proponemos que podría regular los mismos procesos en la neurogénesis
adulta.Wnt5a, es un ligando Wnt no canónico que se ha visto involucrado en la regulación de
la diferenciación y desarrollo morfológico neuronal en estadios embrionarios. Con esto,
nosotros proponemos que el ligando Wnt5a regula la diferenciación y desarrollo morfológico
de las nuevas neuronas generadas a partir de AHPs. El objetivo es estudiar la función del
ligando Wnt5a sobre la neurogénesis hipocampal adulta in vitro e in vivo, utilizando ligando
recombinante Wnt5a obtuvimos un aumento en la proliferación de los AHPs in vitro.
Utilizando un vector lentiviral que expresa un shENA contra el ligando Wnt5a (shWnt5a), se
redujo la expresión de Wnt5a en AHPs y en hipocampo de ratón. Determinamos que el
shWnt5a disminuye la diferenciación y desarrollo morfológico en neuronas generadas a partir
de AHPs sugiriendo que participaría en la regulación neurogénesis adulta.
Neurogenesis is the process of generating new neurons in the adult brain. This process takes place in the sub-granular zone (SGZ) in the dentate gyrus (DG) of the hippocampus and in the sub ventricular zone (SVZ) in the wall of the lateral ventricles. Neuronal stem cells also called adult hippocampal progenitors (AHPs) are present in the SGZ, proliferate and give rise to granular neurons. These cells migrate through the granule cell layer (GCL), extending their dendrites to the molecular layer (ML) by integrating into the hippocampal circuit contributing to learning and memory dependent on the hippocampus. AHPs can be isolated from the adult brain and studied in vitro. Among several mechanisms that modulate neurogenesis, little is known about the specific role of non-canonical Wnt signaling pathways. As the non-canonical Wnt pathway participates in the morphological development and differentiation of neurons in embryonic stages we propose that it could regulate the same processes in adult neurogenesis. Wnt5a is a non-canonical Wnt ligand that has been involved in regulation of neuronal differentiation and morphological development in embryonic stages. With this, we propose that Wnt5a regulates the differentiation and morphological development of the new neurons generated from AHPs. The aim is to study the role of the Wnt5a ligand on adult hippocampal neurogenesis in vitro and in vivo. Using Wnt5a recombinant ligand we obtained an increase in the proliferation of AHPs in vitro. Using a lentiviral vector expressing a shRNA against Wnt5a ligand (shWnt5a), Wnt5a expression in AHPs and mouse hippocampus was reduced. We determined that shWnt5a decreases the differentiation and morphological development in neurons generated from AHPs suggesting that it would participate in the regulation of adult hippocampal neurogenesis.
Neurogenesis is the process of generating new neurons in the adult brain. This process takes place in the sub-granular zone (SGZ) in the dentate gyrus (DG) of the hippocampus and in the sub ventricular zone (SVZ) in the wall of the lateral ventricles. Neuronal stem cells also called adult hippocampal progenitors (AHPs) are present in the SGZ, proliferate and give rise to granular neurons. These cells migrate through the granule cell layer (GCL), extending their dendrites to the molecular layer (ML) by integrating into the hippocampal circuit contributing to learning and memory dependent on the hippocampus. AHPs can be isolated from the adult brain and studied in vitro. Among several mechanisms that modulate neurogenesis, little is known about the specific role of non-canonical Wnt signaling pathways. As the non-canonical Wnt pathway participates in the morphological development and differentiation of neurons in embryonic stages we propose that it could regulate the same processes in adult neurogenesis. Wnt5a is a non-canonical Wnt ligand that has been involved in regulation of neuronal differentiation and morphological development in embryonic stages. With this, we propose that Wnt5a regulates the differentiation and morphological development of the new neurons generated from AHPs. The aim is to study the role of the Wnt5a ligand on adult hippocampal neurogenesis in vitro and in vivo. Using Wnt5a recombinant ligand we obtained an increase in the proliferation of AHPs in vitro. Using a lentiviral vector expressing a shRNA against Wnt5a ligand (shWnt5a), Wnt5a expression in AHPs and mouse hippocampus was reduced. We determined that shWnt5a decreases the differentiation and morphological development in neurons generated from AHPs suggesting that it would participate in the regulation of adult hippocampal neurogenesis.
Notas
Tesis (Bioquímica, Magíster en Bioquímica)
Este trabajo de Tesis ha sido financiado Proyecto FONDECYT Nº1150933, título: "Adult neurogenesis, hippocampal plasticity and memory: Regulation by Wnt signalling"
Este trabajo de Tesis ha sido financiado Proyecto FONDECYT Nº1150933, título: "Adult neurogenesis, hippocampal plasticity and memory: Regulation by Wnt signalling"
Palabras clave
Ligandos, Neurogénesis, Células Madre Neuronales