Descripción del proyecto
La función del centrosoma en la neurogénesis
El centrosoma es un orgánulo que actúa como el centro de organización de microtúbulos de las células animales y participa en funciones como la división celular, la formación de cilios y la migración. Las mutaciones en proteínas asociadas al centrosoma producen enfermedades encefálicas, pero todavía se desconocen los mecanismos subyacentes a este proceso. El proyecto financiado con fondos europeos NeuroCentro estudiará las funciones fundamentales de las proteínas del centrosoma específicas de las neuronas con el fin de comprender el fenotipo de las mutaciones que es específico para el encéfalo. La investigación aprovechará un descubrimiento reciente del equipo del proyecto sobre unas nuevas proteínas de unión al ARN asociadas al centrosoma en células madre neuronales humanas con unas asociaciones importantes y selectivas con la heterotopía periventricular (HP), un trastorno de migración neuronal. Por último, los investigadores intentarán aplicar herramientas genéticas avanzadas para recuperar la función del centrosoma y corregir los defectos que provoca la HP.
Objetivo
The centrosome is a crucial cellular organelle involved in many functions especially during development where it acts to regulate key processes, such as cell division, cilia formation and migration. While many mutations in centrosome-associated proteins lead to diseases often predominantly affecting the brain, the basis for this specificity is in most cases not known. Likewise, basic aspects of centrosome biology, such as the role of RNAs at the centrosome, are largely unknown. Our recent discovery of novel centrosome-associated proteins in human neural stem cells revealed specific RNA-binding proteins at the sub-distal appendages of centrosomes with significant and selective associations to periventricular heterotopia (PH), a neuronal migration disorder. This provides a unique entry point to explore, in the first part of this project, fundamental questions associated with the role of RNAs and RNA-binding proteins at the centrosome and their contribution to neurodevelopmental disorders. In the second part, we will explore changes in centrosome composition from NSCs to young migratory neurons and identify the role of the centrosome in neuronal subtype-specific migration modes using the novel centrosome protein Akna as entry point. In the third part, we will utilize our advanced tools for dCas9 multiplexed transcriptional engineering to restore centrosome function of ectopic neurons and revert migration defects causing PH. These rescue attempts will be extended to later stages of development aiming to revert differentiated glia, the ependymal cells, to radial glial cells, that serve as guides for migrating neurons. This work will thus tackle fundamental functions of neural-specific centrosome proteins, laying the basis to understand the brain-specific phenotype of mutations in factors that are widely expressed but predominantly affect the brain.
Ámbito científico
Programa(s)
Régimen de financiación
ERC-ADG - Advanced GrantInstitución de acogida
85764 Neuherberg
Alemania