Description du projet
Le rôle du centrosome dans la neurogenèse
Le centrosome est un organite qui sert de centre d’organisation des microtubules de la cellule animale, et il est impliqué dans des fonctions comme la division cellulaire ou la formation et la migration des cils. Les mutations des protéines associées au centrosome entraînent des maladies cérébrales, mais les mécanismes de ce processus nous sont inconnus. Le projet NeuroCentro, financé par l’UE, étudiera les fonctions fondamentales des protéines du centrosome spécifiques aux neurones afin de comprendre le phénotype des mutations spécifiques au cerveau. La recherche s’appuie sur les découvertes de l’équipe d’un projet récent concernant de nouvelles protéines de liaison à l’ARN associées au centrosome dans les cellules souches neurales humaines, avec des associations significatives et sélectives avec l’hétérotopie périventriculaire (PH), un trouble de la migration neuronale. En définitive, les chercheurs tenteront d’appliquer des outils génétiques avancés pour restaurer la fonction du centrosome et pour inverser les défauts provoquant la PH.
Objectif
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.
Champ scientifique
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Régime de financement
ERC-ADG - Advanced GrantInstitution d’accueil
85764 Neuherberg
Allemagne