Inestabilidad genómica inducida por la activación sostenida de la vía de señalización WNT/β-catenina en células progenitoras neuronales humanas
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2019
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es
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Universidad Andrés Bello
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Resumen
El Trastorno del Espectro Autista (TEA) es un grupo de trastornos del neurodesarrollo, que incluye un lenguaje retrasado o anormal, déficits en la interacción social y conductas e intereses restringidos y/o repetitivos y se estima que en Estados Unidos la tasa de prevalencia del TEA es de 1 de cada 59 niños. La etiología del TEA es variable, hasta un 20% a 25% de los casos se deben a anomalías genéticas raras como mutaciones que van desde variantes de un solo nucleótido, variaciones en el número de copias y aberraciones cromosómicas como deleciones, duplicaciones y traslocaciones. Los factores ambientales son responsables del 40% a 50% de los casos de TEA, pero se estima que la gran mayoría de los casos proviene de influencias genéticas multifactoriales: en estos casos, la vulnerabilidad genética puede interactuar con influencias ambientales. Recientemente, en un estudio de 9 set de datos de exomas de individuos con TEA y discapacidad intelectual, se identificó mutaciones de novo – aquellas que no están presentes en la madre o en el padre – estas se encontraron en una red de interacción proteínas-proteína donde se enriquecen componentes asociados a funciones sinápticas, remodelación de cromatina y señalización Wnt/β-catenina. Dentro de los genes mayormente afectados por mutaciones de novo se encuentran tres en particular: CHD8 y DYRK1A, ambos genes tienen la capacidad de modular negativamente a la vía de señalización Wnt/β-catenina y PTEN el cual es un gen blanco de la vía de señalización. Estos tres genes no solamente se han asociado al aumento del riesgo de desarrollar TEA, sino que también al desarrollo de macrocefalia, una de las co-morbilidades medicas más frecuentes asociadas al TEA. A nivel molecular, se ha reportado que la sobre activación de la vía de señalización Wnt/β-catenina en el desarrollo del cerebro puede aumentar el área cortical del cerebro debido a la estimulación proliferativa en células progenitoras neurales y que una estimulación aberrante puede conducir a estrés transcripcional desencadenando eventos de inestabilidad genómica en genes altamente expresados. Nuestro laboratorio estudia el efecto de la ganancia de función de la vía Wnt/β-catenina como inductor de eventos de inestabilidad genómica, incluyendo translocaciones cromosómicas. En este estudio proponemos que la activación sostenida de la vía de señalización produce inestabilidad genómica en progenitores neuronales humanos. Utilizando como modelo de estudio la línea celular Human Neural Stem Cells (H9 hESC-Derived), se examinó los efectos de la activación sostenida de la vía sobre la generación de quiebres en el ADN mediante el ensayo de electroforesis alcalina de célula única (Alkaline Comet Assay). Se espera que los resultados de la presente memoria de título aporten en esclarecer uno de los mecanismos involucrados en el desarrollo del TEA.
Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders, which includes delayed or abnormal language, deficits in social interaction and restricted and/or repetitive behaviors and interests, and it is estimated that in the United States the prevalence rate of ASD is 1 in 59 children. The etiology of ASD is variable, up to 20% to 25% of cases are due to genetic anomalies, including mutations that occur at a single nucleotide, number of DNA copies and chromosomal aberrations such as deletions, duplications and translocations. Environmental factors are responsible for 40% to 50% of cases of ASD, but it is estimated that most cases of multifactorial genetic influences, in these cases, genetic capacity can interact with environmental influences. It has been recently found in a study of 9 exome datasets of individuals with ASD and intellectual disability, that de novo mutations have been identified - those that are not present in the mother or in the father - have been found in a protein network protein, where components associated with synaptic functions, chromatin remodeling and Wnt/β-catenin signaling are enriched. Among the genes most affected by de novo mutations are three in particular: CHD8 and DYRK1A, both genes can negatively modulate the Wnt/β-catenin signaling pathway and PTEN that is a target gene of the pathway. These three genes have not only been associated with the increased risk of developing ASD, but also with the development of macrocephaly, one of the most frequent medical comorbidities in ASD. At the molecular level, it has been reported that activation of the Wnt/β-catenin signaling pathway in brain development can increase the cortical area of the brain due to the proliferative capacity of neural progenitor cells and that transcriptional stress can induce genomic instability events in highly expressed genes. Our laboratory is conducting studies to address the effect of the gain-of-the function of the Wnt/β-catenin pathway as inducer of genomic instability events, including chromosomal translocations. In this study, we proposed that a sustained activation of the Wnt/β-catenin signaling pathway induces genomic instability in human neuronal progenitors. Using the human neural stem cell line (H9 hESC-Derived) as a study model, the effects of sustained activation of the pathway of generation of DNA breaks were examined by the single-cell alkaline electrophoresis assay (comet assay alkaline). It is expected that the results of this present title report contribute to clarify one of the mechanisms involved in the development of ASD.
Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders, which includes delayed or abnormal language, deficits in social interaction and restricted and/or repetitive behaviors and interests, and it is estimated that in the United States the prevalence rate of ASD is 1 in 59 children. The etiology of ASD is variable, up to 20% to 25% of cases are due to genetic anomalies, including mutations that occur at a single nucleotide, number of DNA copies and chromosomal aberrations such as deletions, duplications and translocations. Environmental factors are responsible for 40% to 50% of cases of ASD, but it is estimated that most cases of multifactorial genetic influences, in these cases, genetic capacity can interact with environmental influences. It has been recently found in a study of 9 exome datasets of individuals with ASD and intellectual disability, that de novo mutations have been identified - those that are not present in the mother or in the father - have been found in a protein network protein, where components associated with synaptic functions, chromatin remodeling and Wnt/β-catenin signaling are enriched. Among the genes most affected by de novo mutations are three in particular: CHD8 and DYRK1A, both genes can negatively modulate the Wnt/β-catenin signaling pathway and PTEN that is a target gene of the pathway. These three genes have not only been associated with the increased risk of developing ASD, but also with the development of macrocephaly, one of the most frequent medical comorbidities in ASD. At the molecular level, it has been reported that activation of the Wnt/β-catenin signaling pathway in brain development can increase the cortical area of the brain due to the proliferative capacity of neural progenitor cells and that transcriptional stress can induce genomic instability events in highly expressed genes. Our laboratory is conducting studies to address the effect of the gain-of-the function of the Wnt/β-catenin pathway as inducer of genomic instability events, including chromosomal translocations. In this study, we proposed that a sustained activation of the Wnt/β-catenin signaling pathway induces genomic instability in human neuronal progenitors. Using the human neural stem cell line (H9 hESC-Derived) as a study model, the effects of sustained activation of the pathway of generation of DNA breaks were examined by the single-cell alkaline electrophoresis assay (comet assay alkaline). It is expected that the results of this present title report contribute to clarify one of the mechanisms involved in the development of ASD.
Notas
Tesis (Ingeniero en Biotecnología)
proyecto Fondecyt N°1180848
proyecto Fondecyt N°1180848
Palabras clave
Vía de Señalización Wnt, Autismo Infantil, Investigaciones